Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We and others have shown that insulin acutely suppresses glucose production in fasting nondiabetic humans and dogs, by both a direct hepatic effect and an indirect (extrahepatic) effect, and in diabetic dogs by an indirect effect alone. In type 2 diabetes, there is resistance to insulin's ability to suppress hepatic glucose production, but it has not previously been determined whether the resistance is primarily at the level of the hepatocyte or the peripheral tissues. To determine whether the diabetic state reduces the direct effect of insulin in humans, we studied nine patients with untreated type 2 diabetes who underwent three studies each, 4-6 weeks apart. 1) Portal study (POR): intravenous tolbutamide was infused for 3 h with calculation of pancreatic insulin secretion from peripheral plasma C-peptide. 2) Peripheral study (PER): equidose insulin was infused by peripheral vein. 3) Half-dose peripheral insulin study (1/2 PER): matched peripheral insulin levels with study 1. In all studies, glucose was clamped at euglycemia, glucose turnover was measured with the constant specific activity method, and 3-[3H]glucose was purified by high-performance liquid chromatography. Peripheral insulin was lower in POR versus PER but slightly higher in POR versus 1/2 PER, although most of the difference could be accounted for by higher proinsulin levels in POR (stimulated by tolbutamide). Calculated portal insulin was approximately 1.3-fold higher in POR versus PER and approximately 2.2-fold higher in POR versus 1/2 PER. In the final 30 min of the clamp, glucose production reached a lower steady-state level in PER than in POR (4.0 +/- 0.4 vs. 5.3 +/- 0.5 pmol(-1) x kg(-1) x min(-1), P < 0.05), despite the higher hepatic insulin level in POR. In contrast with our studies in nondiabetic individuals, glucose production was not more suppressed at steady state in POR versus 1/2 PER (5.3 +/- 0.4 micromol x kg(-1) x min(-1)), despite much higher hepatic insulin levels in POR. In conclusion, this is the first study in patients with type 2 diabetes to characterize insulin resistance to the acute direct suppressive effect of insulin on hepatic glucose production.
Diabetes 1999 Mar
PMID:Resistance to insulin's acute direct hepatic effect in suppressing steady-state glucose production in individuals with type 2 diabetes. 1007 58

We sought to elucidate the role of the portal vein afferents in the sympathetic response to hypoglycemia. Laparotomy was performed on 27 male Wistar rats. Portal veins were painted with either 90% phenol (denervation group [PDN]) or 0.9% saline solution (sham-operated group [SHAM]). Rats were chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion). After a recovery period of 5 days, animals were exposed to a hyperinsulinemic-hypoglycemic clamp, with glucose infused either portally (POR) or peripherally (PER). In all animals, systemic hypoglycemia (2.48+/-0.09 mmol/l) was induced via jugular vein insulin infusion (50 mU x kg(-1) x min(-1)). Arterial plasma catecholamines were assessed at basal (-30 and 0 min) and during sustained hypoglycemia (60, 75, 90, and 105 min). By design, portal vein glucose concentrations were significantly elevated during POR versus PER (4.4+/-0.14 vs. 2.5+/-0.07 mmol/l; P<0.01, respectively) for both PDN and SHAM. There were no significant differences in arterial glucose or insulin concentration between the four experimental conditions at any point in time. When portal glycemia and systemic glycemia fell concomitantly (SHAM-PER), epinephrine increased 12-fold above basal (3.75+/-0.34 and 44.56+/-6.1 nmol/l; P<0.001). However, maintenance of portal normoglycemia (SHAM-POR) caused a 50% suppression of the epinephrine response, despite cerebral hypoglycemia (22.2+/-3.1 nmol/l, P<0.001). Portal denervation resulted in a significant blunting of the sympathoadrenal response to whole-body hypoglycemia (PDN-PER 27.6+/-3.8 nmol/l vs. SHAM-PER; P<0.002). In contrast to the sham experiments, there was no further suppression in arterial epinephrine concentrations observed during PDN-POR versus PDN-PER (P = 0.8). These findings indicate that portal vein afferent innervation is critical for hypoglycemic detection and normal sympathoadrenal counterregulation.
Diabetes 2000 Jan
PMID:Portal vein afferents are critical for the sympathoadrenal response to hypoglycemia. 1061 43

Hyperinsulinemia during exercise in people with diabetes requiring exogenous insulin is a major clinical problem. The aim of this study was to assess the significance of portal vein versus arterial insulin to hepatic effects of hyperinsulinemia during exercise. Dogs had sampling (artery, portal vein, and hepatic vein) and infusion (vena cava and portal vein) catheters and flow probes (hepatic artery and portal vein) implanted >16 days before a study. Protocols consisted of equilibration (-130 to -30 min), basal (-30 to 0 min), and treadmill exercise (0-150 min) periods. Somatostatin was infused and glucagon and insulin were replaced in the portal vein to achieve basal arterial and portal vein levels at rest and simulated levels during the first 60 min of exercise. From 60 to 150 min of exercise, the simulated insulin infusion was sustained (C; n = 7), modified to selectively create a physiologic increment in arterial insulin (Pe; n = 7), or altered to increase arterial insulin as in Pe but with a concomitant increase in portal insulin (PePo; n = 7). Euglycemic clamps were performed in all studies. Portal and arterial insulin were 15 +/- 2 and 4 +/- 1 micro U/ml (mean +/- SE of all groups), respectively, at t = 60 min in all groups. Insulin levels were unchanged for the remainder of the exercise period in C. Arterial insulin was increased from 3 +/- 1 to 14 +/- 2 micro U/ml, whereas portal insulin did not change in Pe after t = 60 min. Arterial insulin was increased from 3 +/- 1 to 15 +/- 2 micro U/ml, and portal insulin was increased from 16 +/- 3 to 33 +/- 3 micro U/ml in PePo after t = 60 min. Endogenous glucose production (R(a)) rose similarly from basal during the first 60 min of exercise in all groups (mean +/- SE of all groups was from 2.2 +/- 0.1 to 6.8 +/- 0.5 mg. kg(-1). min(-1)). The increase in R(a) was sustained for the remainder of the exercise period in C. R(a) was suppressed by approximately 40%, but only after 60 min of hyperinsulinemia, and by approximately 20% after 90 min of hyperinsulinemia in Pe. In contrast, the addition of portal venous hyperinsulinemia caused approximately 90% suppression of R(a) within 20 min and for the remainder of the experiment in PePo. Measurements of net hepatic glucose output were similar to R(a) responses in all groups. Arterial free fatty acids (FFAs), a stimulus of R(a), were increased to 1,255 +/- 258 micro mol/l in C but were only 459 +/- 67 and 312 +/- 42 micro mol/l in Pe and PePo, respectively, by 150 min of exercise. Thus, during exercise, the exquisite sensitivity of R(a) to hyperinsulinemia is due entirely to portal venous hyperinsulinemia during the first 60 min, after which peripheral hyperinsulinemia may control approximately 20-40%, possibly as a result of inhibition of the exercise-induced increase in FFA.
Diabetes 2004 Feb
PMID:Suppression of endogenous glucose production by mild hyperinsulinemia during exercise is determined predominantly by portal venous insulin. 1474 77

Depression is highly prevalent in diabetics and is associated with poor glucose regulation and increased risk of diabetic complications. Identification and effective treatment of comorbid depression are increasingly being considered essential components of clinical care of diabetics. In the present study, the antidepressant activity of quercetin (50 and 100 mg/kg, i.p.), a bioflavonoid, was evaluated using the Porsolt forced swimming-induced behavioral despair test in control and 6-week-streptozotocin-induced diabetic mice. The effect of quercetin was compared with that of the classical antidepressants fluoxetine (5 mg/kg, i.p.) and imipramine (15 mg/kg, i.p.). Streptozotocin-induced diabetic mice exhibited prolonged immobility duration during the test as compared with age-matched control mice. Quercetin dose-dependently reduced the immobility period in diabetic mice, and this effect was comparable to that of fluoxetine (5 mg/kg, i.p.) and imipramine (15 mg/kg, i.p.). Fluoxetine and imipramine significantly lowered the immobility time in naive mice also, but quercetin failed to induce any antidepressant activity in naive mice. The results of our preliminary study indicate that quercetin has the potential to be employed as a therapy for depression associated with diabetes.
 ...
PMID:Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-induced diabetic mice. 1497 50

Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation. Dogs received 0.36 units/kg s.c. regular human insulin (n = 6) or 1 mg (2.8 units/kg) or 2 mg (5.6 units/kg) dry-powder human inhaled insulin (n = 3 and 6, respectively). Postinhalation of inhaled insulin (1 or 2 mg), arterial insulin levels quickly rose to a maximum of 55 +/- 6 or 92 +/- 9 microU/ml, respectively, declining to typical fasting levels by 3 h. Portal levels were lower than arterial levels at both doses, while deep venous levels were intermediate to arterial and portal levels. In contrast, subcutaneous insulin was associated with a delayed and lower peak arterial concentration (55 +/- 8 microU/ml at 64 min), requiring 6 h to return to baseline. Peak portal levels for subcutaneous insulin were comparable to those for 1 mg and significantly less than those for 2 mg inhaled insulin, although portal area under the curve (AUC) was comparable for the subcutaneous and 2-mg groups. The highest insulin levels with subcutaneous administration were seen in the deep venous circulation. Interestingly, the amount of glucose required for maintaining euglycemia was highest with 2 mg inhaled insulin. We conclude that plasma insulin AUC for the arterial insulin level (muscle) and hepatic sinusoidal insulin level (liver) is comparable for 2 mg inhaled insulin and 0.36 units/kg subcutaneous insulin. In addition, arterial peak concentration following insulin inhalation is two times greater than subcutaneous injection; however, the insulin is present in the circulation for half the time.
Diabetes 2004 Apr
PMID:Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection. 1504 1

Several lines of evidence have indicated that the prevalence of psychiatric disorders in diabetic subjects is higher than that in the general population, however, little information is available on the effects of antidepressants in diabetes. In the present review, we summarized the effect of diabetes on the central serotonergic systems and the efficacy of serotonergic antidepressants. Streptozotocin-induced diabetic mice showed prolonged duration of immobility compared to non-diabetic mice in the tail suspension test. This behavioral change was unrelated to the transient increases in blood glucose concentrations or decreased body weights by diabetes. Fluoxetine, a selective serotonin (5-HT) reuptake inhibitor, reduced the duration of immobility in both non-diabetic and diabetic mice. However, a selective 5-HT1A receptor antagonist WAY-100635 reversed the antidepressant-like effect of fluoxetine only in non-diabetic mice. In addition, a 5-HT1A receptor agonist 8-OH-DPAT reduced the duration of immobility in non-diabetic mice, but not in diabetic mice. These results suggest a possibility that the antidepressant-like effect mediated by the activation of 5-HT1A receptors may be attenuated by diabetes.
 ...
PMID:[Diabetes attenuates the antidepressant-like effect mediated by the activation of 5-HT1A receptors in the mouse tail suspension test]. 1529 Dec 46

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. A lack of understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin-induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia compared with control mice. Fluoxetine (10 and 20, but not 5 mg/kg, i.p.) injected into diabetic mice produced an antinociceptive effect in both the tail-immersion and hot-plate assays. The percentage maximum possible effect (% MPE) produced by fluoxetine (20 mg/kg, i.p.) was significantly lower in diabetic mice than in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose-dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT(1A/1B) receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT(2A/2C) receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/kg, i.p., a selective 5-HT(3) receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT(1) and 5-HT(2) receptors, but not through 5-HT(3) receptors, in the chronic pain associated with streptozotocin-induced diabetic neuropathy. Further, the potentiation of the antinociceptive effect of fluoxetine by pindolol indicates the usefulness of a combination of an antidepressant and a 5-HT(1A/1B) receptor antagonist in the treatment of diabetic neuropathic pain in humans.
 ...
PMID:Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice. 1533 46

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that can lead to hepatic fibrosis and cirrhosis. Portal fibrosis in the absence of NASH, called isolated portal fibrosis (IPF), has received less attention and has not been classified as a spectrum of NAFLD. The aims of this study were to determine the prevalence of IPF in subjects undergoing gastric bypass surgery, to identify biochemical variables associated with IPF, and to assess the metabolic syndrome as defined by the AdultTreatment Panel III criteria. We analyzed liver biopsies from 195 morbidly obese subjects after excluding all other causes of liver disease. The prevalence of fatty liver (FL) only, IPF, and NASH was 30.3%, 33.3%, and 36.4%, respectively. Several biochemical parameters significantly trended across the 3 groups, with IPF falling between FL and NASH. Hyperglycemia was the only metabolic parameter associated with NASH (OR, 5.4; 95% CI, 2.4-12; P < .0001) and IPF (OR, 2.8; 95% CI, 1.2-6.5; P = .01). Subjects with diabetes had the greatest risk for NASH (OR, 8; 95% CI, 3.3-19.7; P < .0001) and IPF (OR, 4.3; 95% CI, 1.6-11.6; P = .003). The metabolic syndrome was identified in 78.5% of subjects, and a significant trend for the number of metabolic criteria was observed across the spectrum of FL, IPF, and NASH. In conclusion, a significant subset of morbidly obese individuals has portal fibrosis in the absence of NASH that is associated with glycemic dysregulation. Therefore, IPF should be considered a spectrum of NAFLD that may prelude NASH in morbid obesity.
 ...
PMID:Portal fibrosis and hepatic steatosis in morbidly obese subjects: A spectrum of nonalcoholic fatty liver disease. 1536 53

Physicians and surgeons who treat patients with gastrointestinal or hepatic disease must prescribe the most appropriate diagnostic tests, together with an accurate prognosis and effective and safe therapy. This paper examines the best modalities of surgical treatment for cancer of the pancreas, in an evidence-based approach. Evidence was classified as follows: Grade A : evidence from large randomized controlled trials (RCT) or systematic reviews (including meta-analyses) of multiple randomized trials which collectively have at least as much data as one single well-defined trial. Grade B: evidence from at least one high-quality study of non-randomized cohorts or evidence from at least one high-quality case-control study or one high-quality case series. Grade C: opinions from experts without references or access to any of the foregoing The data were obtained from Medline and from controlled randomized trials listed in the Cochrane Library up to the end of 2003. Two series (grade B) showed the superiority of Whipple over total pancreatectomy, with respective median survival times of 12.6 months and 9.6 months. Extensive lymphadenectomy (grade A) in patients with positive lymph nodes gave significantly better survival than standard resection in one trial, but this was not confirmed in the other trial. Results of pylorus-preserving pancreaticoduodenectomy (PPPD) were not different from those of the Whipple procedure on postoperative mortality, morbidity or survival (grade A). Portal vein resection increased the resectability rate. Post-operative mortality was not increased: survival was not different in four studies and was shorter in another four studies (grade C). Low-dose postoperative erythromycin accelerates gastric emptying if the right gastric artery is preserved (grade A). One trial suggests that pancreaticogastrostomy reduces the risk of pancreatic fistula. The two other trials are controversial and showed no difference. One prospective non randomized study showed that stenting in pancreaticojejunostomy reduces the risk of pancreatic fistulae and intraabdominal abscess. To prevent this risk of pancreatic fistula, six controlled trials involving patients receiving octreotride were performed Three European trials showed a smaller volume of abdominal drainage fluid and an abnormal amylase concentration; however, two American trials failed to demonstrate a significant difference. Occlusion of the pancreatic duct with fibrin glue did not reduce the risk of pancreatic fistula, but increased the risk of developing diabetes. Intraabdominal drainage after pancreatic resection significantly increased post-operative complications (grade A). Surgical resection and reconstruction procedures for pancreatic cancer must be based on evidence-based studies. However, the most important prognostic factor is the surgeon's experience, not only with regard to the post-operative course, but also survival. Specific teaching and training is thus essential.
 ...
PMID:[Evidence based surgery of cancer of head of pancreas]. 1565 35

Because hypoxia may compromise the survival of intraportally transplanted pancreatic islets, we have measured portal blood flow and both portal and hepatic oxygenation in normal and diabetic rats breathing graded inspired oxygen concentrations. Portal blood flow and hepatic tissue oxygenation were measured using a transonic flowmeter and near infrared spectroscopy while gas analysis was carried out on portal venous blood samples. The effects of breathing 13%, 21%, 50%, or 100% oxygen were compared in animals with steptozotocin-induced diabetes and in controls. In diabetic rats breathing 21% oxygen, portal blood flow was significantly lower than in controls (7.2+/-0.7 vs. 9.1+/-0.8 ml/min, p < 0.05). In both groups, breathing 100% oxygen significantly increased portal flow (to 8.4+/-1.0 and 12.2+/-0.7 ml/min, respectively). This effect was not secondary to hepatic arterial vasoconstriction because it was not prevented by hepatic artery ligation. In controls, breathing 100% oxygen increased portal pO2 from 5.0+/-0.9 to 14.4+/-1.4 kPa (p < 0.05) and portal venous oxygen saturation (PSaO2) from 53.9+/-12.1% to 92.9+/-1.4% (p < 0.05), a value not significantly different from peripheral (arterial) saturation. Similarly, in diabetic animals pO2 rose from 5.6+/-0.3 to 11.7+/-0.4 kPa (p < 0.01) and SO2 from 55.5+/-5.2% to 88.5+/-0.6% (p < 0.05). Hepatic oxyhemoglobin rose and deoxyhemoglobin fell reciprocally as a function of the inspired oxygen concentration. Improved hepatic oxygenation observed in animals breathing oxygen-enriched gas mixtures results from an increase in splanchnic blood flow coupled with a marked increase in portal oxygen saturation. This effective arterialization of portal blood may have important consequences for the success of intraportal transplantation of pancreatic islets.
 ...
PMID:Effect of inspired oxygen on portal and hepatic oxygenation: effective arterialization of portal blood by hyperoxia. 1569 Sep 82


<< Previous 1 2 3 4 5 6 Next >>