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Proinsulin C-peptide activates vagus efferent output in rats

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Abstract

The aim of this study was to examine the effect of proinsulin C-peptide on the autonomic nervous systems in rats. Intravenous administration of C-peptide gradually increased electrophysiological activity of the vagus nerves into the stomach and pancreas for at least 90 min. It also slightly increased gastric acid secretion that was suppressed by the treatment with atropine. Intraperitoneal injection of C-peptide did not affect the basal and stress-induced norepinephrine (NE) turnover rate, a biochemical index of sympathetic nerve activity. These results indicate that C-peptide increases parasympathetic nerve activity without affecting sympathetic nerve activity. This could explain, at least in part, the ameliorating effects of C-peptide on impaired cardiac autonomic nerve functions in patients with type 1 diabetes.

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... A plausible method of activating the vagus nerve, improving low HRV and restoring the cholinergic antiinflammatory pathway is the central administration of proinsulin C-peptide, which may have a life-saving effect in critical situations, prevent the cytokine storm, reduce the likelihood of sepsis or pneumonia, myocarditis, heart arrhythmia, ventricular fibrillation or reduce the severity of the pathological progress of these problems. [15] [16] ...
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The "nitric oxide (NO)-pathway" is presumed to be involved in acetylcholine (ACh)- and serotonin (5-hydroxytryptamine, 5-HT)-mediated vasodilatation. In addition, both the 5-HT-induced transient and persistent vasodilator responses in the forearm vascular bed are abolished by the 5-HT3/5-HT4-receptor antagonist ICS 205-930 ([1H]-indol-3-carbonic-acid-tropine-ester HCl, tropisetron). We studied 5-HT-mediated vasodilatation in the forearm vascular bed of normotensive volunteers, using venous occlusion plethysmography. Intraarterial (i.a.) infusions of 5-HT, ACh, and sodium nitroprusside (SNP) all caused an increase in forearm blood flow (FBF). Single infusions of ondansetron and granisetron also caused an increase in FBF. Infusion of the NO scavenger and guanylate-cyclase antagonist methylene blue (MB) did not change FBF, whereas the arginine analogue NG-monomethyl-L-arginine (L-NMMA) caused a decrease in FBF, which became less pronounced when infusions were repeated. Unlike ICS 205-930, concomitant infusions of the selective 5-HT3-receptor antagonists ondansetron (OND) and granisetron (GRAN) did not antagonize the transient or persistent vasodilator responses to 5-HT. These findings suggest the involvement of a 5-HT4-receptor. L-NMMA and MB both reduced the persistent vasodilator response to 5-HT, indicating involvement of the NO pathway. Neither MB nor L-NMMA influenced the endothelium-independent vasodilator response to SNP. ACh-induced vasodilatation was markedly potentiated by MB but was not affected by L-NMMA. The mechanism by which MB enhances the vasodilator response to ACh remains unclear.
Article
To examine the effects of brain cytokines on the sympathetic nervous system, norepinephrine (NE) turnover in peripheral organs (spleen, lung, diaphragm, pancreas, heart, liver, kidney, and interscapular brown adipose tissue) was assessed after intraperitoneal or intracerbroventricular administrations of human recombinant interleukin (IL)-1 beta and IL-6 in rats. An intraperitoneal injection of IL-1 (1 microgram/rat) accelerated NE turnover in the spleen, lung, diaphragm, and pancreas without appreciable effects in other organs examined. When IL-1 was injected intracerebroventricularly at much lower doses (1-100 ng/rat), a dose-dependent increase in NE turnover was observed in the spleen, lung, diaphragm, and pancreas. IL-6 did not affect NE turnover in every organ examined, even when it was given at much higher doses, 100 micrograms/rat and 100 ng/rat for intraperitoneal and intracerebroventricular injections, respectively. In contrast to tissue NE turnover, plasma corticosterone level was increased after the administration of IL-6 as well as IL-1, regardless of the site of administration. These results suggest that central IL-1, but not IL-6, increases sympathetic nerve activity in some specific organs, whereas both cytokines are effective for adrenocortical activation. A possible role of the sympathetic nervous system in physiological and immune responses to central IL-1 was discussed.
Article
Intermittent footshock (FS) suppresses immune function of spleen cells. To determine if the autonomic nervous system mediates this immunosuppression in spleen cells, we tested whether cutting the splenic nerve, which depletes splenic norepinephrine levels by 98-100% and eliminates catecholamine fibers, blocks the effects of stress. Splenic nerve sections, sham operations, or no surgery were performed on male Sprague-Dawley rats. Ten days later, rats were injected with sheep red blood cells (SRBC). Three days later, rats were placed in a chamber equipped with a shock grid. Foot shock (1.6 mA) was administered for 5 s on a VI 3.5 min schedule for 60 min. Each FS was preceded by a 15-s warning tone. Controls were treated identically except for the FS. The next day spleen cells were harvested and the number of IgM plaque-forming cells (PFCs) determined. For the sham and unoperated control animals, the number of PFCs was reduced for the stressed animals relative to the nonstressed controls, and there was no effect of the sham surgeries. In contrast, there was no difference between the stressed and nonstressed groups in which the splenic nerve had been sectioned, and their PFC response was comparable to the controls. Next we examined the effects of FS on the proliferative response to mitogens (PHA and ConA) following splenic nerve sections or sham operations. One week following surgery, animals were given a 60-min session of FS or exposed to the chamber/tone without FS. Rats were then killed, spleens harvested, and the proliferative response to mitogens determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Autonomous neuropathy in patients with diabetes is associated with dysmotility and abdominal discomfort. The disturbances resemble to some extent those seen in patients with functional dyspepsia. To gain further insight into the disorders, we compared patients with long-standing diabetes, patients with functional dyspepsia, and healthy individuals with respect to abdominal symptoms, width of gastric antral area, and autonomic nerve function. We investigated 42 type I diabetic outpatients by structured interview for abdominal discomfort, ultrasonography of the gastric antrum, assessment of vagal and sympathetic nerve function by respiratory sinus arrhythmia and skin conductance, and measurement of blood sugar and HbA1c. Immediately after a standard meal of soup with meat, 21 (50%) of the 42 patients with diabetes complained of abdominal discomfort (pain, bloating, fullness), which was significantly less frequent (95% CI of difference 0.03-0.5) than previously seen in patients with functional dyspepsia (76%), and significantly more frequent (95% CI of difference 0.3-0.6) than that seen in healthy individuals (4%). Bloating was the most marked postprandial complaint. Mean fasting antral area was significantly wider in patients with diabetes (mean 4.9 cm2, SD 1.7) compared to healthy individuals (mean 3.5 cm2, SD 1.2), 95% CI of difference 0.6-2.2 cm2. Mean postprandial antral area was 14.8 cm2 (SD 4.6) in the patients with diabetes, which is insignificantly wider than in patients with functional dyspepsia (mean 13.0 cm2, SD 4.0) but significantly wider (95% CI of difference 1.9-6.5 cm2) than that seen in healthy individuals (mean 10.6 cm2, SD 3.8). The mean respiratory sinus arrhythmia was 0.7 beats/min (SD 0.7) in the patients with diabetes, which was insignificantly lower than that seen in patients with functional dyspepsia (2.1 beats/min, SD 4.5), and significantly lower (99% CI of difference 3.8-7.1 beats/min) compared to healthy individuals (6.2 beats/min, SD 3.8). It is concluded that patients with diabetes have a wider gastric antrum and more discomfort after a meal than healthy individuals. Compared to patients with functional dyspepsia, patients with diabetes have a wider postprandial antrum but fewer symptoms. The very low vagal tone seen in patients with diabetes may play an important role in the pathogenesis of their gastric motility disturbance and postprandial abdominal discomfort.
Article
In order to determine the possible influence of C-peptide on nerve function, 12 insulin-dependent diabetic (IDDM) patients with symptoms of diabetic polyneuropathy were studied twice under euglycaemic conditions. Tests of autonomic nerve function (respiratory heart rate variability, acceleration and brake index during tilting), quantitative sensory threshold determinations, nerve conduction studies and clinical neurological examination were carried out before and during a 3-h i.v. infusion of either C-peptide (6 pmol.kg-1.min-1) or physiological saline solution in a double-blind study. Plasma C-peptide concentrations increased from 0.11 +/- 0.02 to 1.73 +/- 0.04 nmol/l during C-peptide infusion. Clinical neurological examination quantitative sensory threshold evaluations and nerve conduction measurements failed to detect significant changes between C-peptide and saline study periods. Respiratory heart rate variability increased significantly from 13 +/- 1 to 20 +/- 2% during C-peptide infusion (p < 0.001), reaching normal values in five of the subjects; control studies with saline infusion did not alter the heart rate variability (basal, 14 +/- 2; saline, 15 +/- 2%). A reduced brake index value was found in seven patients and increased significantly during the C-peptide infusion period (4.6 +/- 1.0 to 10.3 +/- 2.2%, p < 0.05) but not during saline infusion (5.9 +/- 2 to 4.1 +/- 1.1%, NS). It is concluded that short-term (3-h) infusion of C-peptide in physiological amounts may improve autonomic nerve function in patients with IDDM.
Article
The role cardiac autonomic neuropathy (CAN) plays in diabetes is not well known. The aim of this study was to identify the factors involved in CAN in diabetic patients. One hundred patients, 44 insulin-dependent (IDDM) and 56 non-insulin-dependent (NIDDM), were investigated, using five standard tests. Three of these tests were for parasympathetic control (cardiac response to the lying-to-standing, deep breathing, and Valsalva tests), and the other two measured sympathetic control (testing for orthostatic hypotension and evaluating heart and blood pressure response to the handgrip test). Results were compared to those found in a series of 40 healthy volunteers. An age-adjusted comparison with the controls, showed that 34 patients had one abnormal parasympathetic test, 23 had two, and 6 patients had three. Cardiac parasympathetic neuropathy was thus present in 63% of the patients. The handgrip test was completed by 84 diabetic patients. There was evidence of orthostatic hypotension and/or an abnormal cardiac response to the handgrip in 15 of these patients, who all had a parasympathetic abnormality as well. There was no significant association between the type of diabetes and the presence of CAN. The duration of diabetes was significantly longer in patients with CAN (9.3 +/- 0.9 years) (p < 0.01) than in those with all three parasympathetic tests normal (5.8 +/- 0.9 years) (p < 0.01). The HbA1c level was also higher in patients with CAN than in those with three normal parasympathetic tests (9.95 +/- 0.35% versus 8.17 +/- 0.42%, p < 0.005). There was a significant association between the presence of retinopathy, observed by angiofluorography, and the presence of peripheral neuropathy confirmed by the electrophysiological investigation and the presence of CAN (p < 0.001). However, more than half the patients without retinopathy or nephropathy had CAN, and 11 of the 31 patients with a normal electrophysiological investigation also had CAN. Eighteen patients (6 IDDM) without retinopathy and nephropathy, who had been diabetic for less than 2 years, also had CAN. This study shows that CAN occurs early and is frequently found in a population of unselected diabetic patients. Metabolic factors may play an important role in its occurrence. CAN is significantly associated with the presence of retinopathy, which suggests that an impairment of autonomic peripheral blood flow control might be a contributing factor in the formation of microvascular lesions.
Article
The relationship between the changes of active oxygen metabolism and blood flow and the formation, progression, and recovery of lesions was examined in the gastric mucosa of rats treated once with compound 48/80, a mast cell degranulator. Gastric mucosal lesions appeared 0.5 hr after compound 48/80 treatment, became worst at 3 hr, and recovered fairly well at 12 hr. Increases in gastric mucosal lipid peroxide content and xanthine oxidase and myeloperoxidase activities and decreases in gastric mucosal vitamin E and hexosamine contents and Se-dependent glutathione peroxidase activity occurred with the formation and progression of gastric mucosal lesions. These changes were attenuated with the recovery of the lesion. Gastric mucosal nonprotein SH content decreased with the formation of gastric mucosal lesions, and this decreased SH content returned to near the original level with lesion progression. No changes in gastric mucosal superoxide dismutase and catalase activities occurred with the formation, progression, and recovery of gastric mucosal lesions. Gastric mucosal blood flow decreased with the formation of gastric mucosal lesions, and this decreased blood flow recovered with lesion progression. Serum serotonin concentration, an index of mast cell degranulation, increased with the formation of gastric mucosal lesions, and this increased serotonin level was attenuated with lesion progression and recovery. Pretreatment with ketotifen, a connective tissue mast cell stabilizer, prevented the formation of gastric mucosal lesions, the increases of gastric mucosal lipid peroxide content, xanthine oxidase and myeloperoxidase activities, and serum serotonin level; and the decreases of gastric mucosal nonprotein SH content, glutathione peroxidase activity, and blood flow found at 0.5 hr after compound 48/80 treatment. These results indicate that the changes of gastric mucosal active oxygen metabolism and blood flow are closely related to the formation, progression, and recovery of gastric mucosal lesions in rats with a single compound 48/80 treatment. The present results also suggest that this compound 48/80-induced gastric mucosal injury could be a kind of ischemia-reperfusion-induced injury occurring through degranulation of connective tissue mast cells.
Article
C-peptide, a cleavage product from the processing of proinsulin to insulin, has been considered to possess little if any biological activity other than its participation in insulin synthesis. Injection of human C-peptide prevented or attenuated vascular and neural (electrophysiological) dysfunction and impaired Na+- and K+-dependent adenosine triphosphate activity in tissues of diabetic rats. Nonpolar amino acids in the midportion of the peptide were required for these biological effects. Synthetic reverse sequence (retro) and all–d–amino acid (enantio) C-peptides were equipotent to native C-peptide, which indicates that the effects of C-peptide on diabetic vascular and neural dysfunction were mediated by nonchiral interactions instead of stereospecific receptors or binding sites.
Article
The thyrotropin-releasing hormone (TRH) analog, RX 77368, (p-Glu-His-(3,3'-dimethyl)-Pro-NH2) injected intracisternally (i.c.) at low doses increases gastric mucosal blood flow through vagal cholinergic and calcitonin gene-related peptide dependent pathways. The influence of the mast cell stabilizer, ketotifen, on i.c. injection of RX 77368 (1.5 ng)-induced changes in gastric mucosal blood flow (hydrogen gas-clearance technique), gastric acid secretion and mean arterial pressure was studied in urethane-anesthetized rats. RX 77368 increased gastric blood flow by 131% and systemic arterial pressure by 11 mm Hg and decreased gastric mucosal vascular resistance by 54% whereas acid secretion was not altered within the 30 min period post injection. Ketotifen had no effect on these basal parameters but abolished i.c. RX 77368-induced increased gastric mucosal blood flow and decreased gastric vascular resistance. These data suggest that mast cells may be part of the peripheral mechanisms involved in vagal gastric hyperemia induced by TRH analog injected i.c. at a low dose.
Article
To assess the possible role of urocortin, a recently identified neuropeptide related to corticotropin-releasing factor (CRF), in modulation of peripheral immune functions, the effects of intracranially administrated urocortin on the proliferative activity of splenic lymphocytes were examined in rats. Intracerebroventricular (i.c.v.) injection of urocortin (1 ng) produced a marked decrease in the proliferative response of splenocytes to a mitogen. The suppressive effect of urocortin was abolished by pretreatment with a ganglionic blocking agent (chlorisondamine) or a beta-adrenergic receptor antagonist (propranolol), but not by adrenalectomy. These results suggest that urocortin is an important neuropeptide involved in the brain control of peripheral immune functions such as stress-induced immunosuppression, and that the suppressive effect of urocortin is mediated by the sympathetic nervous system.
Article
Efferent nerve signals were recorded from the central cut end of the small nerve filament dissected from the sympathetic nerve innervating the white adipose tissue (WAT) of epididymis, inter scapular brown adipose tissue (BAT), pancreas, liver, adrenal medulla, and vagus nerve innnervating the pancreas and liver. Injection of leptin (2 ng, 0.2 ml) into the white adipose tissue of the either side of the epididymis evoked reflex activation of the sympathetic nerve activity and suppression in vagus nerve activity. These observations suggest that leptin sensors in the white adipose tissue of the epididymis play a role in reflex regulation of metabolic functions of the body through the modulatory change in sympathetic and vagal outflow.
Article
The C-peptide of proinsulin is important for the biosynthesis of insulin but has for a long time been considered to be biologically inert. Data now indicate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to a G protein-coupled surface receptor, with subsequent activation of Ca(2+)-dependent intracellular signaling pathways. The association rate constant, K(ass), for C-peptide binding to endothelial cells, renal tubular cells, and fibroblasts is approximately 3. 10(9) M(-1). The binding is stereospecific, and no cross-reaction is seen with insulin, proinsulin, insulin growth factors I and II, or neuropeptide Y. C-peptide stimulates Na(+)-K(+)-ATPase and endothelial nitric oxide synthase activities. Data also indicate that C-peptide administration is accompanied by augmented blood flow in skeletal muscle and skin, diminished glomerular hyperfiltration, reduced urinary albumin excretion, and improved nerve function, all in patients with type 1 diabetes who lack C-peptide, but not in healthy subjects. The possibility exists that C-peptide replacement, together with insulin administration, may prevent the development or retard the progression of long-term complications in type 1 diabetes.
Article
Recent studies have indicated that proinsulin C-peptide shows specific binding to cell membrane binding sites and may exert biological effects when administered to patients with Type 1 diabetes mellitus. This study was undertaken to determine if combined treatment with C-peptide and insulin might reduce the level of microalbuminuria in patients with Type 1 diabetes and incipient nephropathy. Twenty-one normotensive patients with microalbuminuria were studied for 6 months in a double-blind, randomized, cross-over design. The patients received s.c. injections of either human C-peptide (600 nmol/24 h) or placebo plus their regular insulin regimen for 3 months. Glycaemic control improved slightly during the study and to a similar extent in both treatment groups. Blood pressure was unaltered throughout the study. During the C-peptide treatment period, urinary albumin excretion decreased progressively on average from 58 microg/min (basal) to 34 microg/min (3 months, P < 0.01) and it tended to increase, but not significantly so, during the placebo period. The difference between the two treatment periods was statistically significant (P < 0.01). In the 12 patients with signs of autonomic neuropathy prior to the study, respiratory heart rate variability increased by 21 +/- 9% (P < 0.05) during treatment with C-peptide but was unaltered during placebo. Thermal thresholds were significantly improved during C-peptide treatment in comparison to placebo (n = 6, P < 0.05). These results indicate that combined treatment with C-peptide and insulin for 3 months may improve renal function by diminishing urinary albumin excretion and ameliorate autonomic and sensory nerve dysfunction in patients with Type 1 diabetes mellitus.
Article
Ghrelin, a novel growth-hormone-releasing peptide, was discovered in rat and human stomach tissues. However, its physiological and pharmacological actions in the gastric function remain to be determined. Therefore, we studied the effects of rat ghrelin on gastric functions in urethane-anesthetized rats. Intravenous administrations of rat ghrelin at 0.8 to 20 microgram/kg dose-dependently increased not only gastric acid secretion measured by a lumen-perfused method, but also gastric motility measured by a miniature balloon method. The maximum response in gastric acid secretion was almost equipotent to that of histamine (3 mg/kg, i.v.). Moreover, these actions were abolished by pretreatment with either atropine (1 mg/kg, s.c.) or bilateral cervical vagotomy, but not by a histamine H(2)-receptor antagonist (famotidine, 1 mg/kg, s.c.). These results taken together suggest that ghrelin may play a physiological role in the vagal control of gastric function in rats.
Article
Proinsulin C-peptide has been reported to have some biological activities and to be possibly involved in the development of diabetic microangiopathy. In the present study, we examined the effects of C-peptide on the mitogen-activated protein kinase pathway in LEII mouse lung capillary endothelial cells. Stimulation of the cells with C-peptide increased both p38 mitogen-activated protein kinase (p38MAPK) and extracellular signal-regulated kinase (ERK1/2) activities and activity-related site-specific phosphorylation of the respective kinases in a concentration-dependent manner, but failed to activate c-Jun N-terminal kinase. Stimulation of the cells with C-peptide also induced site-specific phosphorylation of cAMP response element (CRE)-binding protein (CREB)/activating transcription factor 1 (ATF1), and thereby binding of these transcription factors to CRE. Among three CREB kinases tested, phosphorylation of mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2) was induced after stimulation with C-peptide. The phosphorylation of CREB, ATF1 and MAPKAP-K2 were inhibited by SB203580, a p38MAPK inhibitor, but not by PD98059, an ERK kinase inhibitor. These results indicate that C-peptide activates p38MAPK followed by MAPKAP-K2 to enhance DNA-CREB/ATF1 interactions.
Article
This review will focus on recent advances in the field of diabetic neuropathy, with an emphasis on distal symmetric sensory and sensorimotor polyneuropathy. Some new information in the areas of diabetic amyotrophy and diabetic autonomic neuropathy will also be reviewed. The pathogenesis of diabetic neuropathy is multifactorial. There is increasing evidence to link abnormalities in the polyol pathway to the pathogenesis of diabetic neuropathy. In addition, there appear to be abnormalities of nerve regeneration and of sodium and calcium channels. Aldose reductase inhibitors have shown promise in animal models for reversing neuropathy if started early and used for a sufficient time, but those used to date in human trials are probably not of sufficient potency. Neurotrophic factors and vascular endothelial growth factor both also show promise. Specific recommendations and pathways for diabetic foot care have been devised. Lamotrigine and bupropion represent new treatments for neuropathic pain. The role of impaired glucose tolerance is being explored as it relates to polyneuropathy. An increasing understanding of the pathogenetic mechanisms holds out promise for the effective treatment of diabetic neuropathy. The early detection of abnormal glucose metabolism is particularly important, as treatments will probably be most effective if administered early in the course of the neuropathy, when abnormalities of peripheral nerves are more likely to be reversible.
Article
Studies have demonstrated that proinsulin C-peptide stimulates the activities of Na(+),K(+)-ATPase and endothelial nitric oxide synthase, both of which are enzyme systems of importance for nerve function and known to be deficient in type 1 diabetes. The aim of this randomized double-blind placebo-controlled study was to investigate whether C-peptide replacement improves nerve function in patients with type 1 diabetes. Forty-nine patients without symptoms of peripheral neuropathy were randomized to either 3 months of treatment with C-peptide (600 nmol/24 h, four doses s.c.) or placebo. Forty-six patients (15 women and 31 men, aged 29 years, diabetes duration 10 years, and HbA(1c) 7.0%) completed the study. Neurological and neurophysiological measurements were performed before and after 6 and 12 weeks of treatment. At baseline the patients showed reduced nerve conduction velocities in the sural nerve (sensory nerve conduction velocity [SCV]: 50.9 +/- 0.70 vs. 54.2 +/- 1.2 m/s, P < 0.05) and peroneal nerve (motor nerve conduction velocity: 45.7 +/- 0.55 vs. 53.5 +/- 1.1 m/s, P < 0.001) compared with age-, height-, and sex-matched control subjects. In the C-peptide treated group there was a significant improvement in SCV amounting to 2.7 +/- 0.85 m/s (P < 0.05 compared with placebo) after 3 months of treatment, representing 80% correction of the initial reduction in SCV. The change in SCV was accompanied by an improvement in vibration perception in the patients receiving C-peptide (P < 0.05 compared with placebo), whereas no significant change was detectable in cold or heat perception. In conclusion, C-peptide administered for 3 months as replacement therapy to patients with early signs of diabetic neuropathy ameliorates nerve dysfunction.
Article
In this paper, the current knowledge about the role of histamine in the control of gastric acid secretion is reviewed. In particular, we focus this topic into three sections considering the recent insights on: histamine receptor subtypes involved in gastric acid secretion, the interplay between neuronal-hormonal-paracrine pathways and the cerebral histaminergic control of gastric secretion. From the careful perusal of scientific literature, the fundamental role of histamine as local stimulator of gastric acid secretion via H(2) receptors is fairly confirmed while for the H(3) receptor only a minor modulating role is hypothesized. An undisputed function of ECL cells as controllable source of histamine within the so-called gastrin-ECL cell-parietal cell axis is generally proposed and the intriguing possibility of a remote control of gastric secretion via H(3) receptors is also suggested.
Article
Proinsulin C-peptide treatment can partially prevent nerve dysfunction in type 1 diabetic rats and patients. This could be due to a direct action on nerve fibers or via vascular mechanisms as C-peptide stimulates the nitric oxide (NO) system and NO-mediated vasodilation could potentially account for any beneficial C-peptide effects. To assess this further, we examined neurovascular function in streptozotocin-induced diabetic rats. After 6 weeks of diabetes, rats were treated for 2 weeks with C-peptide to restore circulating levels to those of nondiabetic controls. Additional diabetic groups were given C-peptide with NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) co-treatment or scrambled C-peptide. Diabetes caused 20 and 16% reductions in sciatic motor and saphenous sensory nerve conduction velocity, which were 62 and 78% corrected, respectively, by C-peptide. L-NNA abolished C-peptide effects on nerve conduction. Sciatic blood flow and vascular conductance were 52 and 41%, respectively, reduced by diabetes (P < 0.001). C-peptide partially (57-66%) corrected these defects, an effect markedly attenuated by L-NNA co-treatment. Scrambled C-peptide was without effect on nerve conduction or perfusion. Thus, C-peptide replacement improves nerve function in experimental diabetes, and the data are compatible with the notion that this is mediated by a NO-sensitive vascular mechanism.
Article
Patients with type 1 (insulin-dependent) diabetes show reduced skeletal muscle blood flow and coronary vasodilatory function despite intensive insulin therapy and good metabolic control. Administration of proinsulin C-peptide increases skeletal muscle blood flow in these patients, but a possible influence of C-peptide on myocardial vasodilatory function in type 1 diabetes has not been investigated. Ten otherwise healthy young male type 1 diabetic patients (Hb A1c 6.6%, range 5.7-7.9%) were studied on two consecutive days during normoinsulinemia and euglycemia in a double-blind, randomized, crossover design, receiving intravenous infusion of C-peptide (5 pmol.kg-1.min-1) for 120 min on one day and saline infusion on the other day. Myocardial blood flow (MBF) was measured at rest and during adenosine administration (140 microg.kg-1.min-1) both before and during the C-peptide or saline infusions by use of positron emission tomography and [15O]H2O administration. Basal MBF was not significantly different in the patients compared with an age-matched control group, but adenosine-induced myocardial vasodilation was 30% lower (P < 0.05) in the patients. During C-peptide administration, adenosine-stimulated MBF increased on average 35% more than during saline infusion (P < 0.02) and reached values similar to those for the healthy controls. Moreover, as evaluated from transthoracal echocardiographic measurements, C-peptide infusion resulted in significant increases in both left ventricular ejection fraction (+5%, P < 0.05) and stroke volume (+7%, P < 0.05). It is concluded that short-term C-peptide infusion in physiological amounts increases the hyperemic MBF and left-ventricular function in type 1 diabetic patients.
Article
There is increasing evidence for biological functions of human C-peptide. Recently, we have described that proinsulin C-peptide increases nutritive capillary blood flow and restores erythrocyte deformability in type 1 diabetic patients, whereas it has no such effect in non-diabetic subjects. The aim of the current study was to elucidate cellular mechanisms of this vasodilator effect in vitro by measuring the nitric oxide (NO)-mediated increase of cGMP production in a RFL-6 reporter cell assay and by demonstrating endothelial calcium influx with the Fluo-3 technique. C-peptide increased the release of NO from endothelial NO synthase (eNOS) in bovine aortic endothelial cells in a concentration- and time-dependent manner. At physiological concentrations of C-peptide, endothelial NO production was more than doubled (208+/-12% vs control; p<0.001). The NO release was abolished by the inhibitor of NO synthase N(G)-nitro-L-arginine or when Ca(2+) was removed from the medium superfusing the endothelial cells. C-peptide stimulated the influx of Ca(2+) into endothelial cells. No change in Ser-1179 phosphorylation of eNOS was detected after 6.6nM C-peptide. C-peptide did not change eNOS mRNA levels after 1, 6 or 24h. These data indicate that C-peptide is likely to stimulate the activity of the Ca(2+)-sensitive eNOS by increasing the influx of Ca(2+) into endothelial cells. We suggest that this effect may contribute to the increase in skin and muscle blood flow previously demonstrated in human in vivo.
Article
Diabetes is an increasingly common disorder which causes and contributes to a variety of central nervous system (CNS) complications which are often associated with cognitive deficits. There appear to be two types of diabetic encephalopathy. Primary diabetic encephalopathy is caused by hyperglycemia and impaired insulin action, which evolves in a diabetes duration-related fashion and is associated with apoptotic neuronal loss and cognitive decline. This appears to be particularly associated with insulin-deficient diabetes. Secondary diabetic encephalopathy appears to arise from hypoxic-ischemic insults due to underlying microvascular disease or as a consequence of hypoglycemia. This type of cerebral diabetic complication is more common in the type 2 diabetic population. Here, we will review the clinical and experimental data supporting this conceptual division of diabetic CNS complications and discuss the underlying metabolic, molecular, and functional aberrations.
Article
In contrast to earlier views, new data indicate that proinsulin C-peptide exerts important physiological effects and shows the characteristics of an endogenous peptide hormone. C-peptide in nanomolar concentrations binds specifically to cell membranes, probably to a G-protein coupled receptor. Ca(2+)- and MAP-kinase dependent signalling pathways are activated, resulting in stimulation of Na(+), K(+)-ATPase and endothelial nitric oxide (NO) synthase, two enzyme systems known to be deficient in diabetes. C-peptide may also interact synergistically with insulin signal transduction. Studies in intact animals and in patients with type 1 diabetes have demonstrated multifaceted effects. Thus, C-peptide administration in streptozotocin-diabetic animals results in normalization of diabetes-induced glomerular hyperfiltration, reduction of urinary albumin excretion and diminished glomerular expansion. The former two effects have also been observed in type 1 diabetes patients given C-peptide in replacement dose for up to 3 months. Peripheral nerve function and structure are likewise influenced by C-peptide administration; sensory and motor nerve conduction velocities increase and nerve structural changes are diminished or reversed in diabetic rats. In patients with type 1 diabetes, beneficial effects have been demonstrated on sensory nerve conduction velocity, vibration perception and autonomic nerve function. C-peptide also augments blood flow in several tissues in type 1 diabetes via its stimulation of endothelial NO release, emphasizing a role for C-peptide in maintaining vascular homeostasis. Continued research is needed to establish whether, among the hormones from the islets of Langerhans, C-peptide is the ugly duckling that--nearly 40 years after its discovery--may prove to be an endogenous peptide hormone of importance in the treatment of diabetic long-term complications.
Proinsulin C-peptide activates CRE binding proteins through the p38 MAP kinase pathway in mouse lung capillary endothelial cells
Proinsulin C-peptide activates CRE binding proteins through the p38 MAP kinase pathway in mouse lung capillary endothelial cells. Biochem J 2002; 366, 737-744.
tissue NE contents (ng/g organ) were determined. The κ is a fractional turnover rate obtained by changes in NE content Values are means ± SEM for 6 rats
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Subsequently, tissue NE contents (ng/g organ) were determined. The κ is a fractional turnover rate obtained by changes in NE content Values are means ± SEM for 6 rats.
Evidence that shock-induced immuno suppression is mediated by adrenal hormones and peripheral β-adrenergic receptors
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  • Dt Lysle
  • Bj Kucicski
  • Bs Rabin
Cunnick JE, Lysle DT, Kucicski BJ, Rabin BS. Evidence that shock-induced immuno suppression is mediated by adrenal hormones and peripheral β-adrenergic receptors. Pharmacol Biochem Behev 1990; 36: 641-651.