Glucose tolerance in elderly patients does not deteriorate during anesthesia and surgical stress

This study evaluated the glucose tolerance of elderly subjects compared with that of younger subjects under surgical stress. During surgery, glucose 0.1 g·kg⁻¹ was administrated i.v. to the elderly group, aged 66–83 years (n=11, mean 73.5±5.9) and the control group, aged 19–64 years (n=11, mean 50.9±15.1), all of whom were scheduled for lower abdominal surgery and had a normal range of fasting blood sugar and glycosylated hemoglobin (HbA_1C). Between 3 and 90min after glucose loading, the blood glucose levels of the control group increased more than those in the elderly group, and at 10 and 15 min those in the control group showed a significantly greater increase than those in the elderly group (P<0.05). Serum insulin concentrations increased at 3 and 5 min, but no significant difference was observed between the two groups. Cortisol and catecholamines also showed no significant difference between groups. It was concluded that glucose tolerance in elderly subjects does not deteriorate during lower abdominal surgery.     

Ileal Interposition Improves Glucose Tolerance in Low Dose Streptozotocin-treated Diabetic and Euglycemic Rats

Background  The surgical treatment for obesity promotes massive weight loss and early improvement in co-morbid conditions such as type-2 diabetes. Because surgically mediated glycemic improvements are immediate, the mechanisms involved appear to be weight loss independent. Ileal interposition has been used to gain understanding of the relative role that the lower intestine plays in mediating metabolic improvement. Here, we report that ileal interposition is sufficient for improving glucose tolerance in a low-dose streptozotocin-treated diabetic rat model as well as in normal rats with no effect on body weight. Methods  Male Long–Evans rats were treated with streptozotocin (35 mg/kg) or left untreated and then received sham or ileal interposition. Body weight was measured as well as glucose and insulin tolerance. Plasma insulin and gut hormones were measured during the glucose tolerance test. Results  Streptozotocin treatment resulted in hyperglycemia within 48 h after treatment. Diabetic rats with ileal interposition showed improvement in glucose tolerance as early as 4 weeks after surgery compared to sham (p < 0.05). By 11 weeks after surgery glucose and insulin tolerance was markedly improved in interposed-diabetic compared to sham-diabetic rats (p < 0.05). Normal non-diabetic rats showed improved glucose tolerance after ileal interposition compared to sham (p < 0.05). Insulin secretion was increased in interposed rats following glucose administration (p < 0.05). The ileal-derived hormones glucagon like peptide-1 (GLP-1), peptide YY (PYY), and glucagon were all significantly elevated in the ileal interposed rats (p < 0.01). Gastric inhibitory polypeptide (GIP) was unchanged. In neither study did body weight between the surgical groups differ at any time point. Conclusions  Ileal interposition effectively improves glucose tolerance in streptozotocin-diabetic and euglycemic rats. Enhanced insulin secretion can explain the lowered glucose concentrations in euglycemic rats following ileal interposition. Ileal interposition is associated with dramatically elevated ileal hormones, GLP-1, PYY, and glucagon (p < 0.01) with no change in the duodenal hormone GIP.     

Morbidly Obese Individuals with Impaired Fasting Glucose have a Specific Pattern of Insulin Secretion and Sensitivity: Effect of Weight Loss after Bariatric Surgery

Background: Obesity is often associated with hyper-secrection of insulin. Impaired fasting glucose (IFG) has recently been redefined as a fasting plasma glucose of 5.6-6.9 mmol/L. The aim of this study was to determine whether changes in insulin secretion in morbidly obese persons also commence with normal serum glucose levels. Methods: 32 morbidly obese subjects were studied before and after bariatric surgery. Measurements were made of glucose tolerance (K_G), insulin sensitivity (SI), first-phase insulin release and the disposition index (DI) from a frequently sampled intravenous glucose tolerance test. Result: In morbidly obese subjects, the SI (P<0.01), DI (P<0.01) and first-phase insulin release (P<0.02) started changing with serum glucose levels considered to be normal (5.00-5.28 mmol/L). K_G showed a clear slope according to the baseline glycemia status (P<0.05), and it was significantly related with the DI, both before (r=0.76, P<0.001) and after (r=0.57, P=0.002) surgery. Following surgery, all the variables significantly associated with insulin secretion and insulin sensitivity recovered significantly. The most significant changes occurred in morbidly obese individuals with IFG. Conclusions: Morbidly obese subjects show slopes of insulin sensitivity and insulin secretion in accordance with their baseline serum glucose levels. The fall in first-phase insulin release begins when serum glucose values are considered normal. Morbidly obese persons with the IFG phenotype have a specific pattern of insulin sensitivity and insulin secretion. K_G clearly discriminates the clinical phenotypes, depending on baseline serum glucose levels.     

Regulation of glucose tolerance in patients after liver transplantation: impact of cyclosporin versus tacrolimus therapy

BACKGROUND: We investigated the factors regulating glucose homeostasis in 10 healthy (control) subjects, as well as in stable, long-term, liver-grafted patients receiving monotherapy in the form of either cyclosporin A (n=10) or tacrolimus (n=10). METHODS: We measured insulin sensitivity, first- and second-phase insulin secretion, with a minimal modeling technique based on the analysis of glucose, insulin, and C-peptide profiles during frequently sampled intravenous glucose tolerance tests (FSIGTT). Proinsulin levels, as a marker of beta-cell dysfunction, were measured in the fasting state and during FSIGTT. RESULTS: Glucose and insulin concentrations before and after glucose loading did not differ in liver transplant patients and in control subjects. Fasting C-peptide levels in both liver-grafted groups were higher than in healthy subjects and remained elevated during FSIGTT (P<0.05). Intravenous glucose tolerance [(K(G)), i.e. the slope of the regression of logarithm of the blood glucose concentrations vs. time], insulin sensitivity, and first-phase insulin secretion did not differ in liver-grafted groups and healthy subjects. Second-phase insulin secretion was about 56% higher in liver-grafted patients than in controls (P<0.05). Body mass index was the overall determinant of insulin sensitivity in all groups. CONCLUSIONS: Long-term monotherapy with cyclosporin A or tacrolimus has no deleterious effects on insulin sensitivity, first-phase insulin secretion, and insulin synthesis in liver transplant patients. Normal insulin sensitivity (posthepatic insulin effect) and enhanced second-phase insulin secretion (prehepatic insulin) point to an accelerated hepatic insulin clearance rate in liver transplant patients. Increased hepatic insulin clearance is compensated by enhanced insulin secretion, indicating that insulin clearance is the major determinant of pancreatic function in liver-grafted patients.     

Minimal model analysis in nondiabetic renal transplant recipients with hepatitis C

INTRODUCTION: Epidemiological data suggest that hepatitis C virus (HCV) infection may contribute to the development of posttransplantation diabetes mellitus (PTDM). METHODS: We investigated the glucose metabolism in 19 renal transplant recipients with antiHCV antibodies and without DM according to World Health Organization criteria before or after transplantation. We measured insulin sensitivity (SI), glucose effectiveness (SG), and pancreatic insulin response using the frequently sampled intravenous glucose tolerance test (FSIGTT). SI and SG were estimated using the Bergman minimal model method and pancreatic insulin response was expressed as the area under insulin curve (AUIC) between 0 and 19 minutes. RESULTS: Impaired glucose tolerance was shown in 42% of patients, some (31.5%) in the range of glucose intolerance (KG: 1-1.5) and others (10.5%) in the diabetes range (KG < 1). SI and SG were decreased in 39% and 63% of patients, respectively. Pancreatic insulin response revealed high variation among patients although showing a tendency to be enhanced. CONCLUSIONS: A high number of HCV-positive renal transplant recipients without clinically manifest PTDM have impaired glucose tolerance, which suggests the future development of diabetes in these patients.     

Plasma levels of endothelin-1 in patients with the hepatorenal syndrome after successful liver transplantation

The hepatorenal syndrome (HRS) is characterized by renal vasoconstriction leading to deterioration of renal function in patients with liver disease. A possible role of endothelin-1 (ET-1) in the pathogenesis of HRS has been suggested, but a correlation between ET-1 plasma levels and the development of HRS as well as the recovery from HRS following OLT has not been shown yet. We performed longitudinal measurements of ET-1 plasma levels in four groups of patients, 5 patients with HRS before and after orthotopic liver transplantation (OLT), 10 patients without HRS undergoing OLT, 20 patients with chronic renal failure but without liver disease, and 12 healthy controls. Before OLT, plasma levels of ET-1 were higher in patients with HRS (19.5 ± 8.6 ng/l, P < 0.001; n = 5) compared to patients without HRS (4.9 ± 1.1 ng/l; n = 10), normals (1.2 ± 0.18 ng/l; n = 12), and patients with chronic renal failure (2.4 ± 0.4 ng/l; n = 20). Patients with HRS compared to patients without HRS had higher levels for creatinine (2.42 ± 0.6 vs. 0.89 ± 0.05 mg/dl, P < 0.05), creatinine clearance (107 ± 9 ml/min vs. 44.6 ± 5.5 ml/min, P < 0.001), and bilirubin (11.4 ± 3.8 vs. 3.7 ± 1 mg/dl, P < 0.05) before OLT. Within one week after OLT, there was a rapid decrease in ET-1 levels in patients with HRS while creatinine and bilirubin levels decreased slower. Regression analysis revealed a weak correlation between serum creatinine and ET-1 (r = 0.192, P = 0.04) and a significant correlation between serum bilirubin and ET-1 (r = 0.395, P < 0.001). The means of the ET-1 levels decreases rapidly with improvement of liver function after OLT. Levels of ET-1 correlate with excretory liver function assessed by bilirubin. The fall in ET-1 levels preceding improvement of renal function further strengthens the concept of ET-1 being a causative factor in HRS. Received: 22 July 1999/Revised: 28 January 2000/Accepted: 11 May 2000     

Long-Term Follow-up of Bone Mass after Orthotopic Liver Transplantation: Effect of Steroid Withdrawal from the Immunosuppressive Regimen

Glucocorticoids have been suggested to play a major role in transplantation-related osteopenia. In this study we assess the long-term changes and the effect of steroid withdrawal from the standard immunosuppressive regimen on bone mineral density (BMD) after orthotopic liver transplantation (OLT). Sixty-nine non-osteoporotic patients (20 women, 49 men), aged 48 ± 9.5 years (mean ± SD), and with a follow-up of 58.3 ± 23.2 months (range 24–121 months) were studied. Immunosuppressive treatment consisted of prednisone, cyclosporin A and azathioprine. In 41 patients (group A), prednisone was tapered and withdrawn after 36.2 ± 19.3 months (range 13–79 months), whereas in 28 patients (group B) prednisone was maintained. BMD in the spine (L1–L4) was serially measured by dual-energy X-ray absorptiometry (Hologic QDR 1000w) at baseline, before steroid withdrawal and at the end of study. Age- and sex-matched Z-scores of BMD were calculated. No differences were found in age, body mass index, time since OLT, or baseline BMD between the two groups. BMD had significantly increased in both groups at the end of follow-up period (group A, +8.1 ± 8.7%; group B, +3.2 ± 8.0%, p<0.05). However, the Z-score was significantly higher in group A than in group B at the end of study (–0.44 ± 1.05 vs –0.99 ± 0.77; p<0.05). BMD recovery was lower in pre-OLT biliary cirrhosis patients. Bone mass improvement was independent of the time since OLT in both groups, and of the time of steroid withdrawal in group A. Our data confirm that steroid withdrawal accelerates the recovery of bone mass in patients who have undergone a successful liver transplantation. Received: 17 April 2001 / Accepted: 1 August 2001     

Effects of olprinone on hepatosplanchnic circulation and mitochondrial oxidation in a porcine model of endotoxemia

Purpose This study was performed in order to assess the effects of olprinone, a phosphodiesterase III inhibitor, on hepatic oxygen delivery (DO₂H), oxygen consumption (VO₂H), and mitochondrial oxidation in the liver of a porcine endotoxemia model. Methods Fourteen pigs received continuous infusion of endotoxin via the portal vein for 240 min. From t = 150 to t = 240 min, animals were randomly divided into two groups to receive saline (control [CONT]; n = 7), or olprinone (OLP; n = 7) via the central vein. Results In the OLP group, prior to olprinone treatment at 150 min, endotoxin induced significant decreases in the cardiac index (CI; from 120 ± 31 to 65 ± 13 ml·kg⁻¹·min⁻¹; P < 0.01) and DO₂H (from 3.58 ± 0.81 to 1.55 ± 0.49 ml·kg⁻¹·min⁻¹; P < 0.01), while VO₂H was maintained. After administration of olprinone (from t = 150 to t = 240 min), CI was unchanged, while DO₂H increased from 1.55 ± 0.49 to 1.93 ± 0.38 ml·kg⁻¹·min⁻¹ (P < 0.01) and VO₂H increased from 0.42 ± 0.28 to 0.69 ± 0.38 ml·kg⁻¹·min⁻¹ (P < 0.01). At t = 240 min, the oxidation level of cytochrome aa3 was significantly higher in the OLP group than in the CONT group (OLP, 66.2 ± 19.3% vs CONT, 26.4 ± 17.3%; P < 0.01). Conclusion Our data for this porcine endotoxemia model suggest that olprinone may have beneficial therapeutic effects in restoring not only systemic and hepatic circulation but also mitochondrial oxidation in the liver.     

Effects of nicardipine-induced hypotension on cerebrovascular carbon dioxide reactivity in patients with diabetes mellitus under sevoflurane anesthesia

Purpose The purpose of this study was to examine the effects of nicardipine-induced hypotension on cerebrovascular CO₂ reactivity in patients with diabetes mellitus under sevoflurane anesthesia. Methods Nineteen diabetic patients, and 11 nondiabetic patients (serving as controls), undergoing elective orthopedic, cardiovascular, or thoracic surgery were included in the study. The diabetic patients were divided into three groups according to the antidiabetic therapy they were receiving, i.e., diet therapy (n = 6), oral antidiabetic drugs (n = 7), and insulin (n = 6). Anesthesia was maintained with 1.0 minimum alveolar concentration of sevoflurane. Absolute and relative cerebrovascular CO₂ reactivity was calculated using a 2.5-MHz pulsed transcranial Doppler (TCD) probe for the continuous measurement of mean blood flow velocity in the middle cerebral artery (Vmca). The cerebrovascular CO₂ reactivity was measured both at baseline and during hypotension by increasing the ventilatory frequency by 4 to 7 breaths·min⁻¹. Nicardipine was used to induce hypotension. Results We found that values for the Bispectral index (BSI), baseline mean blood pressure, endtidal CO₂ (Pet_{CO 2}), and Vmca were essentially identical in all patients, irrespective of the type of antidiabetic treatment being taken. Values for absolute and relative CO₂ reactivity in insulin-dependent patients, at both baseline blood pressure and during hypotension, were lower than those in patients in the antidiabetic drug, diet, and control groups (during hypotension, absolute CO₂ reactivity: diet group: 3.2 ± 0.9; oral antidiabetic drug group: 3.2 ± 0.7; insulin group: 1.5 ± 0.6; control group: 3.4 ± 0.8 cm·s⁻¹·mmHg⁻¹, [P < 0.05 insulin group vs the other groups]; relative CO₂ reactivity: diet group, 6.3 ± 1.0; oral antidiabetic drug group, 6.5 ± 0.8; insulin group, 3.5 ± 0.8; control group, 6.5 ± 0.7%·mmHg⁻¹, [P < 0.05 insulin group vs the other groups]. Conclusion We concluded that cerebrovascular CO₂ reactivity in insulin-dependent patients is impaired during nicardipine-induced hypotension under sevoflurane anesthesia.     

Influence of ACE inhibition on glucose tolerance in patients with stable chronic renal failure

ACE inhibitors improve glucose tolerance and insulin sensitivityin hypertensive patients with normal renal function. Hypertensivepatients with renal failure are a high-risk group who are particularlyglucose intolerant and insulin resistant. We have thereforestudied whether ACE inhibition improve glucose tolerance inthis group as well. In a double-blind placebo-controlled crossover study 10 patientswith stable moderate chronic renal failure (mean endogenouscreatinine clearance 40±16 ml/ min/1.73 m² were examined.Patients were randomly allocated to receive either placebo orthe ACE inhibitor perindopril (2 mg/day per os) for 14 days.After 7 days of wash-out they received the alternative medicationsin random order for another 14 days. Before and after each ofthe two treatment periods (day 1 and day 15) an intravenousglucose tolerance test (i.v. GTT) with concomitant determinationof insulin levels was performed. The glucose disappearance rate(K value) was calculated to express changes in glucose tolerance.An i.v. GTT was also performed in a group of healthy volunteers. The mean K value was significantly (P<0.05) lower, i.e. glucosetolerance was impaired, in patients compared with healthy controls.In addition, baseline and peak insulin levels after the i.v.GTT were significantly higher (P<0.05) in patients than inhealthy subjects. The K values in patients before and afterplacebo treatment (1.33±0.31 and 1.41±0.45 respectively)were not significantly different from the values with perindopriltreatment (1.35±0.37 and 1.41±0.48 respectively).Furthermore, no significant differences between placebo andperindopril treatment were found with respect to the insulinresponse to the glucose load. The peak (5 min) insulin concentrationsafter the i.v. glucose load were 49.0±19.2 µU/ml(day 1) and 50.0±24.9 (day 15) with placebo and 49.2±19.3(day 1) and 46.8±17.9 (day 15) with perindopril. Finally,no significant differences between the two treatment periodswere observed with respect to serum lipid, HbA_1C, glucagon,potassium, and creatinine levels, whereas systolic blood pressuredecreased significantly with perindopril treatment. In contrast to hypertensive patients with normal renal function,ACE inhibition does not cause a demonstrable change of glucosetolerance in patients with moderate chronic renal failure.     

Evaluation of glucose tolerance,insulin secretion,and insulin action in patients with primary hyperparathyroidism before and after surgery

Summary Glucose tolerance, insulin secretion, and insulin sensitivity were evaluated in 8 asymptomatic patients with primary hyperparathyroidism (PHPT) before and at least 8 weeks after surgical correction of PHPT by means of the hyperglycemic clamp technique. In addition, 15 sex- and agematched control subjects were investigated for comparative reasons by the same technique. Glucose metabolized (M) during the hyperglycemic clamp was not significantly (NS) different between patients with PHPT and controls (7.9±2.3 vs. 6.3±1.9 mg/kg/min). However, insulin secretion (I) was significantly elevated in patients with PHPT compared to controls (87±17 vs. 45±12 μU/ml,P<0.05). The calculated insulin sensitivity index, (M/I) was significantly reduced in PHPT compared to controls (11.0±2.1 vs. 15.2±1.4 mg/kg/min per μU/ml×100,P<0.05). Comparing patients with PHPT before and after surgery, the M value, which is a measure of glucose tolerance, was not significantly different (7.9±2.3 vs. 7.8±1.5 mg/kg/min). However, insulin secretion was significantly lower after surgical correction of PHPT compared to the preoperative situation (48±9 μU/ml vs. 87±17 μU/7 ml,P<0.01). The calculated M/I rose significantly after surgery compared to the preoperative value (11±2.1 vs. 17.6±2.7 mg/kg/min per μU/ml ×100,P<0.001). We conclude that disturbed carbohydrate metabolism such as insulin hypersecretion and insulin resistance, in patients with PHPT is an early finding in this disease and that these early disturbances in glucose metabolism are, however, fully reversible. Correction of disturbed carbohydrate metabolism in PHPT might be a distinct argument for early surgical intervention in this disease.     

GLP-1 Plays a Limited Role in Improved Glycemia Shortly After Roux-en-Y Gastric Bypass: A Comparison With Intensive Lifestyle Modification

Rapid glycemic improvements following Roux-en-Y gastric bypass (RYGB) are frequently attributed to the enhanced GLP-1 response, but causality remains unclear. To determine the role of GLP-1 in improved glucose tolerance after surgery, we compared glucose and hormonal responses to a liquid meal test in 20 obese participants with type 2 diabetes mellitus who underwent RYGB or nonsurgical intensive lifestyle modification (ILM) (n = 10 per group) before and after equivalent short-term weight reduction. The GLP-1 receptor antagonist exendin_(9–39)-amide (Ex-9) was administered, in random order and in double-blinded fashion, with saline during two separate visits after equivalent weight loss. Despite the markedly exaggerated GLP-1 response after RYGB, changes in postprandial glucose and insulin responses did not significantly differ between groups, and glucagon secretion was paradoxically augmented after RYGB. Hepatic insulin sensitivity also increased significantly after RYGB. With Ex-9, glucose tolerance deteriorated similarly from the saline condition in both groups, but postprandial insulin release was markedly attenuated after RYGB compared with ILM. GLP-1 exerts important insulinotropic effects after RYGB and ILM, but the enhanced incretin response plays a limited role in improved glycemia shortly after surgery. Instead, enhanced hepatic metabolism, independent of GLP-1 receptor activation, may be more important for early postsurgical glycemic improvements.     

Quantitative Ultrasound of Bone and Markers of Bone Turnover in Cushing’s Syndrome

Quantitative ultrasound (QUS) of bone is a valuable tool in the assessment of postmenopausal osteoporosis. QUS and new markers of bone turnover have been poorly assessed in Cushing’s syndrome, however. Twenty-five patients with Cushing’s syndrome (20 women, 3 men; mean age ± SEM: 38 ± 2 years) were studied and compared with 35 age- and sex-matched control patients (mean age ± SEM: 38 ± 2 years). The following variables were measured in both groups: QUS parameters at the heel (BUA; SOS; Stiffness Index, SI); bone mineral density (BMD) at both the lumbar spine (LS) and femoral neck (FN) by dual-energy X-ray absorptiometry; and serum markers of bone turnover (osteocalcin, procollagen type I N- and C-terminal propeptides (PINP and PICP), bone alkaline phosphatase (BAP), procollagen type I C-terminal telopeptide (ICTP) and urinary type I collagen C-telopepetide breakdown products (CTX)). Both BUA and SI were decreased in patients with Cushing’s syndrome (p<0.01) but not SOS (p=0.08). BMD was also strongly decreased in Cushing’s syndrome, at both the LS and FN (p<0.005). The two markers of bone turnover statistically significantly different between the two groups were osteocalcin (mean ± SEM: 3.5 ± 0.7 ng/ml (Cushing’s syndrome) vs 6.4 ± 0.5 ng/ml (controls, p<0.01)) and CTX (mean ± SEM: 148.7 ± 17.1 μg/mmol Cr (Cushing’s syndrome) vs 220.8 ± 22.9 μg/mmol Cr (controls), p<0.05). The areas under the receiver operating characteristic curve (AUC) were 0.72 (BUA), 0.73 (SI), 0.90 (BMD_LS), 0.81 (BMD_FN), 0.83 (osteocalcin) and 0.64 (CTX) respectively. AUC was significantly higher for BMD_LS than for both BUA and SI (p<0.05). Conversely AUC was not statistically significantly different for BMD_FN as compared with either BUA or SI. AUC was also higher for osteocalcin than for other markers of bone turnover. In conclusion, QUS of bone seems to be a relevant tool for assessing bone involvement in Cushing’s syndrome. QUS does have a lower sensitivity compared with DXA, however, and the relevance of QUS cannot be ascertained until some longitudinal data are forthcoming. Except for CTX, the other new markers of bone turnover assessed in this study (PINP, PICP, BAP and ICTP) do not seem of interest in Cushing’s syndrome. Received: February 2000 / Accepted: 24 August 2000     

Effect of low-dose infusion of prostaglandin E1 on vecuronium-induced neuromuscular blockade

The effect of low-dose (20 ng·kg⁻¹·min⁻¹) infusion of prostaglandin E₁ (PGE₁) on vecuronium-induced neuromuscular blockade was studied. The study population consisted of 24 elderly patients (65–75 years old) and 24 younger adult patients (25–56 years old). They were randomly assigned to the control and PGE₁ groups. The steady-state dose requirement (SSDR) of vecuronium was derived from ondemand infusion of the drug which produced a stable twitch height of 20% of its baseline reading, and recovery time after steady-state infusion was defined as the time for recovery from twitch height from 25% to 75%. The patients in the PGE₁ group received an infusion of PGE₁ 20 ng·kg⁻¹·min⁻¹, while those in the control group received an infusion of normal saline. The SSDR (23.2±9.1 and 34.2±5.9 μg·kg⁻¹. hr⁻¹, respectively;P=0.02) was significantly less and the recovery time (35.0±9.5 and 19.9±4.2 min, respectively;P=0.01) was significantly longer in the elderly than in the younger patients. However, low-dose infusion of PGE₁ significantly increased the SSDR (23.2±9.1 to 37.4±3.7 μg· kg⁻¹·hr⁻¹;P=0.01) and shortened the recovery time (35.0±9.5 to 23.5±4.0 min;P=0.02) in elderly patients. We concluded that low-dose infusion of PGE₁ is effective in preventing the prolonged action of vecuronium in elderly patients.     

Effect of Chronic Vitamin D Infusion Upon In Vivo Glucose Disposal

We have previously demonstrated that parathyroid hormone (PTH) infusion decreases glucose disappearance rate (K_g) in vivo. Because in the rodent model used it was not possible to determine whether the PTH itself, the induced hypercalcemia, or both contributed to the glucose intolerance, we examined the effect of vitamin D infusion on insulin-mediated glucose disposal. In this model also hypercalcemia is induced but PTH levels are suppressed. Thirty male Sprague Dawley rats were continuously infused with vit D for 5 days using an Alzet miniosmotic pump, at a rate of 9.7 pmol/hour. Thirty controls were infused with the vehicle alone. On the 5th day, glucose 700 mg/kg and insulin 0.35 U/kg were given as a bolus through the left femoral vein and blood samples were obtained from the right femoral vein just prior to and at 2, 5, 10, and 20 minutes post-glucose/insulin infusion. At the end of 5 days, plasma calcium levels were higher in the vit D-infused rats than in the control rats (12.8 ± 0.1 versus 10.0 ± 0.1 mg/dL, P < 0.01) and rat PTH levels were suppressed (2.1 ± 0.1 versus 62 ± 12 pg/ml, P < 0.01). Glucose levels were higher in the vit D animals only at 5 minutes following glucose/insulin bolus (375 ± 7 versus 350 ± 6 mg/dL, P < 0.01) but at no other time. There were no differences between serum insulin levels at any time. Unlike previous findings in PTH-infused rats, K_g (measured from 2 to 20 minutes following glucose/insulin bolus) was not different between groups (4.5 ± 0.3 versus 4.7 ± 0.2, P= 0.92.) A positive correlation between serum calcium and serum glucose was found only at 5 minutes (r = 0.55, P < 0.01) and only in the vit D animals. The areas under the glucose curves approached statistically significant differences (vit D-infused 5258 ± 142 mg/dL/18 minutes versus control 4947 ± 127, P= 0.06.) Analysis of serum glucose data by two-factor analysis of variance (ANOVA) suggests that the two groups differ slightly in glucose values (P= 0.03) but have parallel K_g. In order to define whether different effects of PTH (1–34) and vit D on intracellular calcium [Ca²⁺]_i levels could partly explain the different effects of PTH and vit D infusion on glucose disposal, we investigated the effect of PTH and vit D infusions on basal and concanavalin A (con A)-stimulated changes in mononuclear [Ca⁺²]_i levels. Following 5 days of PTH, vit D, or control infusion, peripheral mononuclear cells were incubated with 50 μg/ml con A. Changes in [Ca⁺²]_i over 5 minutes were calculated by flow cytometric measurement of the calcium sensitive fluo-3 AM dye. Despite achieving significant and comparable degrees of hypercalcemia in the PTH and vit D infused animals, there were no differences in basal or con A-stimulated [Ca⁺²]_i levels from control. Consequently, we conclude that vit D-induced hypercalcemia associated with suppressed PTH levels has mild affects on glucose homeostasis but does not affect glucose disappearance rate in vivo (K_g) as does hypercalcemia induced by PTH infusion, and that neither chronic PTH infusion nor chronic vit D infusion are associated with long-standing changes in [Ca²⁺]_i levels. Received: 24 March 1998 / Accepted: 29 June 1998     

Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients

Background. Post-transplant diabetes mellitus is a known complication of steroid therapy in renal transplant recipients. Both insulin resistance and insulin deficiency have been shown to be necessary for development of post-transplant diabetes mellitus. It is not known whether recipients with impaired glucose tolerance have similar degree of insulin resistance or deficient insulin response as recipients with post-transplant diabetes mellitus. Methods. To address this question, we used an oral glucose tolerance test to categorize 46 renal transplant recipients on triple immunosuppressive medication to groups with normal glucose tolerance, impaired glucose tolerance or post-transplant diabetes mellitus. Insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp. Insulin response was calculated from the increase in serum insulin concentration during the oral glucose tolerance test. Results. Twenty-five were categorized to normal glucose tolerance, 15 to impaired glucose tolerance and six to post-transplant diabetes mellitus. There were no statistically significant differences between the groups regarding prednisolone dose, azathiprine dose, use of {beta}-blocker, age, gender, weight, waist-hip ratio, body mass index, donor source, smoking habits, or first-degree relatives with histories of diabetes mellitus. The impaired glucose tolerance and post-transplant diabetes mellitus groups showed a significant reduction in insulin-stimulated glucose disposal rate (mg/kg^.min) compared to the normal glucose tolerance group (4.6±1.6 and 3.4±1.3 respectively vs 7.1±2.4, P<0.05). The insulin response (picomol/l) was not different between the normal glucose tolerance and impaired glucose tolerance groups but was significantly reduced in the post-transplant diabetes mellitus group (448±310 and 450±291 respectively vs 170±128, P<0.05).Conclusion. Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients.     

GLP-1 and Changes in Glucose Tolerance following Gastric Bypass Surgery in Morbidly Obese Subjects

Background: It has been proposed, that the dramatic amelioration of type 2 diabetes following Roux-en-Y gastric bypass (RYGBP) could by accounted for, at least in part, by changes in glucagon-like peptide-1 (GLP-1) secretion. However, human data supporting this hypothesis is scarce. Methods: A 12-month prospective study on the changes in glucose homeostasis, and active GLP-1 in response to a standard test meal (STM) was conducted in 34 obese subjects (BMI 49.1±1.0 kg/m²) who had different degrees of glucose tolerance: normal glucose tolerance (NGT, n=12), impaired glucose tolerance (IGT, n=12), and type 2 diabetes (n=10). Results: At 6 weeks after RYGBP, despite the subjects still being markedly obese (BMI 43.5±0.9 kg/m²), fasting plasma glucose and HbA1c decreased in the 3 study groups (P<0.05). Insulin sensitivity improved, but was still abnormal in a comparable proportion of subjects among groups (P=0.717). When insulin secretion was accounted for the prevailing insulin sensitivity, an increase was found in subjects with diabetes (P<0.05) although it remained lower compared to NGT- and IGT-subjects (P<0.01). At 12 months follow-up, no differences among groups were found in the evaluated glucose homeostasis parameters. Compared to baseline, at 6 weeks the incremental AUC_0-120' of active GLP-1 in response to the STM increased in NGT and IGT (P<0.05) but not in subjects with diabetes (P=0.285). However, the GLP-1 response to a STM was comparable among groups at 12 months follow-up (P=0.887). Conclusions: 1) RYGBP was associated with an improvement but not complete restoration of glucose homeostasis at 6 weeks after surgery. 2) GLP-1 is not a critical factor for the early changes in glucose tolerance.     

Normalization of Insulin Sensitivity in the Obese Patient after Stable Weight Reduction with Bilio-Pancreatic Diversion

Insulin resistance is a common feature in obese patients. To evaluate the modifications in insulin sensitivity after a bariatric operation such as Bilio-pancreatic diversion (BPD), three groups of subjects (14 normal controls (N); seven eX-obese patients (X) with at least 2 years at weight-stable conditions after BPD surgery; and eight morbidly obese patients (O)) were studied with intravenous (IVGTT) and oral (OGTT) glucose tolerance tests. The ratio of the area under the curve (AUC) for glucose over that of insulin was used as a measure of insulin sensitivity. All the following tests were conducted as Bonferroni-corrected pairwise t-tests, in case overall ANOVA was significant. No significant difference was found between N and X subjects, while obese patients showed a reduced AUCg/AUCi ratio with respect to the normal controls (O vs N: 0.01164 ± 0.00039 vs 0.02392 ± 0.0039, p < 0.05). IVGTT, AUCs: significant differences were found in each case: N vs X: 0.0591 ± 0.0075 vs 0.1402 ± 0.0399, p < 0.05; N vs O: 0.0591 ± 0.0075 vs 0.0223 ± 0.0031, p < 0.01; X vs O: 0.1402 ± 0.0399 vs 0.0223 ± 0.0031, p < 0.05. IVGTT-derived data were also analyzed using the minimal model of glucose kinetics; with this method, glucose effectiveness was significantly different between normal subject and obese subjects (0.0248 ± 0.00288 vs 0.00905 ± 0.00135 per min, p < 0.001). The insulin sensitivity index was not significantly different between normal and ex-obese subjects, while both of these groups were significantly different from obese patients (N vs O: 12.04 × 10⁻⁵ ± 2.61 × 10⁻⁵ vs 3.29 × 10⁻⁵ ± 0.61 × 10⁻⁵, p < 0.066; X vs O: 16.42 × 10⁻⁵ ± 4.23 × 10⁻⁵ vs 3.29 × 10⁻⁵ ± 0.61 × 10⁻⁵ per min per pM, p < 0.02). In conclusion, the present study indicates that, after a body weight reduction operation capable of almost re-establishing ideal body weight like BPD, obese individuals with a family history of obesity show a normalization of insulin response to glucose load.     

Hepatocellular Glycogen in Alleviation of Liver Ischemia-Reperfusion Injury During Partial Hepatectomy

Background Temporary occlusion of liver blood supply for complex liver operation is common in liver surgery. However, hepatic vascular occlusion will undoubtedly impair liver function. This study was designed to elucidate the effect of hepatocellular glycogen in alleviation of liver ischemia-reperfusion injury during hepatic vascular occlusion for partial hepatectomy. Methods Fifty-seven patients were randomly divided into an experimental group (n = 29) and a control group (n = 28). In the experimental group, patients were given high-concentration glucose intravenously during 24 h before the operation. The hepatic lesion was resected after portal triad clamping in the two groups. Noncancer liver tissue was biopsied to measure hepatic tissue ATP content and change of malondialdehyde (MDA) and superoxide dismutase (SOD). Liver function of all patients was assessed by using an automatic biochemical analysis apparatus before the operation and the first and fifth days after operation. Results The mean hepatic vascular occlusion time in the experimental group was 19.21 ± 4.54 min and in the control group it was 21.04 ± 5.11 min. Hepatic tissue ATP content of the experimental group was significantly higher than that of the control group at the end of hepatic vascular occlusion (2.15 ± 0.39 μmol/g wet tissue vs. 1.33 ± 0.44, p < 0.01) and at the point of 1-h reperfusion (2.19 ± 0.29 μmol/g wet tissue vs. 1.57 ± 0.35, p < 0.01). There was significant difference in SOD activity between the two groups at the end of hepatic vascular occlusion (130.69 ± 30.49 NU/mg pr vs. 97.83 ± 26.23, p < 0.01) and at the point of 1-h reperfusion (139.55 ± 39.88 NU/mg pr vs. 114.74 ± 25.93, p < 0.01). Significant difference was shown in MDA content between the two groups at the end of hepatic vascular occlusion (3.02 ± 0.30 nmol/mg pr vs. 3.99 ± 0.49, p < 0.01) and at the point of 1-h reperfusion (3.81 ± 0.69 nmol/mg pr vs. 5.75 ± 1.17, p < 0.01). In addition, the liver function of the experimental group was significantly better than that of the control group the first and fifth days after the operation (p < 0.01). Conclusions Abundant intracellular glycogen may reduce liver ischemia-reperfusion injury caused by hepatic vascular occlusion. It is beneficial to give a large amount of glucose before a complex liver operation during which temporary occlusion of hepatic blood flow is necessary.     

Metabolism of prostaglandins in porcine liver transplantation with a graft harvested after 30- and 60-minute warm ischemia

The influence of warm ischemia on the metabolism of prostaglandins was investigated using a pig liver transplantation model employing the temporary portal arterialization technique. Eighteen pigs were divided into three groups according to warm ischemia time: 0 min (group I,n=6), 30 min (group II,n=6), and 60 min (group III,n=6). During portal arterialization, the hepatic venous prostaglandin E₂ (PGE₂) level in group III (3356.0±1011.8pg/ml) was significantly higher than that in group I (831.7±182.1pg/ml;P=0.0285). The hepatic venous PGE₂ levels were significantly higher than the arterial counterparts in all groups both at the beginning and during portal arterialization. At 60 min after portal revascularization, the arterial PGE₂ level in group III (886.7±268.0pg/ml) was significantly higher than that in groups I (99.0±18.6 pg/ml;P=0.0116) and II (204.2±65.4pg/ml;P=0.0282). Neither thromboxane B₂ (TXB₂) nor 6-keto PGF_1α showed any significant differences. In conclusion, the intra-operative changes of PGE₂ thus reflected the degree of warm ischemic damage, and PGE₂ could also be released from the graft. On the other hand, the increased levels of TXB₂ and 6-keto PGF_1α were throught to have an extrahepatic origin.