Intermittent versus continuous clodronate administration in postmenopausal women with low bone mass.

The aim of the study was to compare the effects on bone mass and turnover of continuous vs. intermittent clodronate administration on 120 postmenopausal women (average age 61 years) with low bone mass (femoral neck bone mineral density [BMD] of at least -1 SD or more, T-score), with another 30 women as a control group. Participants were given 1800 mg of clodronate every 6 months over 2 years using different treatment patterns: a) two continuous regimens, consisting of a daily oral dose of 400 mg or 100 mg every 10 days by intramuscular injection, the latter being considered continuous because the interval between injections is shorter than the time employed by each bone remodelling unit to complete the resorption phase of a remodelling cycle; and b) two intermittent regimens, consisting of 1800 mg every 6 months administered either as a single 18-h intravenous infusion or by separate infusions of 300 mg over 6 consecutive days. All women, including those in the control group, received calcium and vitamin D supplementation. After 2 years, continuous clodronate regimens caused an increase in BMD both at lumbar spine and proximal femur (L(1-4) BMD = 3.07% and 2.69%; femoral neck = 2.12% and 2.09%, respectively, with intramuscular and oral regimens). Intermittent clodronate administration was associated with a small increase or a stabilization in bone mass (L(1-4) BMD = 0.53% and 1.22%; femoral neck = 0.30% and 0.77%, respectively, with 1- and 6-day intravenous infusion regimens). From the 12th month, changes in spine and femoral neck BMD after continuous regimens were statistically different compared with that obtained with intermittent ones. Twenty-five of the 150 women (16.7%) discontinued the study before the end of the 2-year follow-up, but of these, only 7 dropped out because of adverse events related to the treatment itself. To summarize, intermittent clodronate administration could be a suitable option for the prevention of osteoporosis.

Paget's disease of bone: benefits of neridonate as a first treatment and in cases of relapse after clodronate.

This study assessed the efficacy of 200 mg of aminohexane bisphosphonate (neridronate) administered by intravenous infusion in a single dose or in two separate doses on consecutive days in 32 patients (16 males and 16 females, average age 66 years) affected by active Paget's disease of bone. Fifteen patients had never been treated with any antiresorptive agent and 17 had had unsatisfactory results from a prior clodronate treatment. All of the latter patients had failed to enter a remission stage (i.e., normalization of bone turnover was not reported at any time during treatment) and had had a full relapse within 6 months after clodronate infusion. In the present study bone-specific alkaline phosphatase (bAp), deoxypyridinoline (dPyr), and N- and C-terminal polypeptide of collagen type 1 (Ntx, Ctx) were determined before neridronate administration and at 1, 3, 6, and 12 months thereafter. Basal values of bAp were 51.7 +/- 2.3 microg/L, range 31.7-92.5 (normal range 6.2-23.6). No statistical differences in markers of bone turnover were evident in the basal state between new pagetic patients (bAp = 55.1 +/- 4.1) and those suffering a relapse after clodronate (bAp = 48.8 +/- 2.6). Neridronate induced an average percent change from baseline in excess bAp of 68.0 +/- 4.3 and in excess dPyr, Ntx, and Ctx of 68.1 +/- 11, 60.6 +/- 8.5, and 86.7 +/- 7.8, respectively. Markers of bone resorption declined more slowly in patients treated previously with clodronate, although the average change in percent decrement from baseline in excess bAp as well as in excess of bone resorption markers was not different from that registered in untreated pagetic patients. Response to treatment, defined as a percent decrement from baseline in excess bAp of 50% or more at any time during the 12-month follow-up, was observed in 27 patients (84.4%). Remission (a drop in bAp to within normal range) was achieved in 21 patients (65.6%) and was maintained in 12 at 12-month follow-up, with no significant differences between either 1- or 2-day infusions, or between new pagetic patients and those relapsing after clodronate. In 15 of 21 patients requiring analgesics to alleviate bone pain, pain was reduced or completely alleviated in 8. A slight, short-lived acute phase reaction (fever and/or arthromyalgia) occurred in 6 patients. To summarize, 200 mg of intravenous neridronate, in one or two doses, significantly reduced the biochemical indices of disease activity in the majority of patients, showing a normalization of bAp in more than 60%. We conclude that neridronate can be used safely in the treatment of patients with Paget's disease of bone either as a first bisphosphonate treatment or as retreatment for patients relapsing after clodronate.

Effects of glimepiride on insulin and glucagon release from isolated rat pancreas at different glucose concentrations.

The effects of glimepiride, the newest sulphonylureic compound, on pancreatic insulin and glucagon secretion were studied using the classical, isolated, perfused rat pancrease model. The influence of four different environmental glucose conditions (during a glycaemic stimulus with glucose increasing from 5 to 8.33 mM and at stable 0, 5 and 2.22 mM glucose levels) on the effects of glimepiride was also assessed. At a pharmacological concentration glimepiride strongly stimulated beta-cell activity, producing a characteristic biphasic insulin release with a sharp first-phase secretory peak, followed by a prolonged and sustained second phase. Environmental glucose concentrations markedly influenced the extent, but not the pattern of glimepiride-induced insulin secretion, as hormone release dropped significantly when the glucose level was reduced. Glimepiride failed to influence alpha-cell activity at any of the environmental glycaemic levels.

Cyclical intravenous clodronate in postmenopausal osteoporosis: results of a long-term clinical trial.

We report the results of long-term cyclical clodronate therapy (200 mg IV infusion every 3 weeks) on 235 women with postmenopausal osteoporosis recruited over 6 years. A retrospective analysis of clinical and instrumental findings in 183 postmenopausal osteoporotic patients was used as control data. Clodronate was well-tolerated and compliance was good. Bone mineral density (BMD) increased significantly and the upward trend persisted for all 6 years of therapy (5.69 +/- 0.184%) vs. controls: -1.47% +/- 0.813%, p <0.0001). The increase in BMD was greater in the 145 patients without vertebral fractures before starting clodronate. From year 3 onward clodronate reduced the incidence of new vertebral fractures. In closed subsets of patients and controls monitored for 3 and 4 years, respectively, the number of patients developing new vertebral fractures fell significantly in the clodronate group (two-sided p value = 0.0671 and p <0.0026, respectively). This trend was more marked in patients who were fracture-free at the beginning of each year. Cyclical clodronate is a safe and effective therapy for established osteoporosis, but clinical trials are necessary to compare its efficacy versus continuous therapy and, as in the case of the other bisphosphonates, to investigate its mechanisms of action in depth.

Cyclical clodronate is effective in preventing postmenopausal bone loss: a comparative study with transcutaneous hormone replacement therapy.

An investigative study was carried out for 2 years involving 124 randomly selected early postmenopausal women with spine bone mineral density (BMD) below the mean value of a normal premenopausal subject. After random division into three groups, the first 42 patients were treated with transcutaneous 17-beta-estradiol (50 micrograms daily), the second 42 were treated with cyclical intravenous clodronate (200 mg/month iv infusion), and the third group of 40 (controls) was left untreated. After 2 years, the total drop in BMD within the control group was more than 7% as opposed to the values of -0.14% +/- 0.93 in the estradiol group and 0.67% +/- 0.84 in the clodronate group. A change in BMD of < 1% was considered satisfactory, and this result was obtained in 32% of the controls, in 79% of the estradiol group where the percentage change in BMD moderately correlated with serum estradiol levels (r = 0.399), and in 90% of the clodronate-treated patients, in whom the percentage change in BMD inversely correlated with basal values of markers of bone turnover. Both estrogen and clodronate prevent postmenopausal bone loss. The response to transcutaneous hormone replacement therapy may be influenced by transcutaneous absorption and by a lower sensitivity to estrogen. Response to cyclical clodronate seems to be influenced by the rate of bone turnover. An interdosage interval ranging from 2-4 weeks appears suitable for most patients.

Glucose modulates the amount, but not the kinetics, of insulin released by sulfonylureas.

This study compares the insulin-secretory profiles induced by therapeutical concentrations of four different sulfonylureas--tolbutamide, gliquidone, gliclazide, and glibenclamide--and the amount of hormone released by each under different ambient glucose concentrations, using the isolated perfused rat pancreas model. All four sulfonylureas stimulated B-cell function, but the kinetics varied. Tolbutamide, gliquidone, and gliclazide produced a quick, biphasic release, whereas glibenclamide stimulated a delayed monophasic insulin secretion. Dramatic falls in insulin release were observed when ambient glucose concentrations were lowered. Glucagon release was not influenced by any of the sulfonylureas whatever the metabolic condition, neither directly nor indirectly, via an insulin-mediated paracrine inhibition of A-cell activity.

Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed.

Clodronate and alendronate were compared in 27 patients with active Paget's bone disease. Carboxyterminal crosslinked telopeptide of type I collagen (ICTP) was evaluated as a marker of bone turnover in Paget's bone disease. Group 1. Nineteen patients received clodronate infusions (300 mg/daily) on 5 consecutive days. After 1 year, 12 patients (63%) were still in remission; urinary hydroxyproline (64.8%) and serum alkaline phosphatase (59.4%) were significantly reduced and had returned to normal in 30%. Patients in remission had significantly higher basal values of urinary hydroxyproline. No adverse side effects were observed. Group 2. One year after clodronate, seven relapsing patients retrospectively underwent five consecutive infusions of alendronate (5 mg/daily). Within 12 months, urinary hydroxyproline fell by 74.7%, alkaline phosphatase dropped by 75.2%, osteocalcin by 47.3%, and ICTP by 56.4%. In all patients, urinary hydroxyproline and alkaline phosphatase returned to normal within 3 months and remained within the normal range during the 12-month follow-up. Most patients had mild, short course fever and arthromyalgia. Group 3. Eight newly diagnosed pagetics, received alendronate alone (5 mg/daily for 5 days). All patients responded well to alendronate within the first month. None suffered a relapse during the follow-up. At month 12, urinary hydroxyproline was down by 71.4%, alkaline phosphatase by 75.3%, osteocalcin by 58.1%, and ICTP by 67.4%. In all patients, markers of bone remodeling were in the normal range at the end of the follow-up. Moderate, transitory arthromyalgia, and fever (high and lasting for 7 days in only one case) were observed in half of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes?

This study investigated whether alterations in bone mineral content (BMC) and/or in the phosphate-calcium metabolism exist in non-insulin-dependent diabetes mellitus (NIDDM); whether they are linked to glycaemic control and whether antidiabetic therapy--oral agents or insulin--influences BMC and mineral metabolism. A cross-section assessment compared BMC and mineral metabolism in 60 well-controlled and 50 poorly controlled diabetic patients under oral hypoglycaemic therapy with 50 healthy controls. A longitudinal assessment improved the high glucose levels of the poorly controlled diabetic group either by increasing oral treatment or by adding a bedtime NPH insulin. Glycaemic control, BMC and mineral metabolism were followed-up for 1 year. In NIDDM patients BMC is reduced. This reduction is more marked in poorly controlled diabetic patients. In well-controlled diabetes osteocalcin levels are low. In poorly controlled patients glycosuria, hypercalcuria and parathyroid hyperactivity are present. In both groups vitamins 25(OH)-D, 1,25(OH)2-D and calcitonin levels are normal. Improving metabolic control increased BMC, normalized urinary calcium excretion and parathyroid activity and reduced osteocalcin levels. The type of anti-diabetic therapy does not have any significant effect upon BMC or upon phosphate-calcium metabolism. In conclusion, in NIDDM a hard-to-define osteoblast deficit appears to exist. In poorly controlled diabetes the loss of BMC is aggravated by the negative calcium balance caused by the renal calcium leak. This is due to glucosuric-induced osmotic diuresis and is maintained by parathyroid activation.

[The effect of different "coherent"-type therapeutic plans on bone mineral density and on the incidence of vertebral fractures in advanced osteoporosis]. / Effetto di differenti schemi terapeutici di tipo "coerente" sulla densità minerale ossea e sull'incidenza delle fratture vertebrali nell'osteoporosi avanzata.

Fifty patients with advanced osteoporosis were treated for 2 years with calcitonin+fluoride using cyclic therapeutic regimens. We evaluated their efficacy in recovering bone loss and reducing the rate of vertebral crush fractures. Twenty-seven control patients were treated for one year with calcium+vitamin D supplements. In the 59% of patients who responded to calcitonin the gain in bone mass (dual photon absorptiometry) correlated inversely with urine calcium and hydroxyproline excretion and serum osteocalcin. In the 70% responding to calcitonin+fluoride it correlated positively with serum osteocalcin and alkaline phosphatase and inversely with urine calcium and hydroxyproline excretion. Compared to basal value both coherent regimens resulted in a significant increase (calcitonin: 1.92 +/- 1.8%, p < 0.01; calcitonin+fluoride: 3.7 +/- 1.4%, p < 0.0005) in spinal bone mass but no significant differences emerged between them. The rate of vertebral crush fractures (radiogrammetry) did not very significantly in any group. The gain in bone mass does not predict the risk of vertebral crush fractures.

Therapeutical concentrations of tolbutamide, glibenclamide, gliclazide and gliquidone at different glucose levels: in vitro effects on pancreatic A- and B-cell function.

In the classical model of isolated perfused rat pancreas four commonly used sulfonylureas--tolbutamide, glibenclamide, gliquidone and gliclazide--were investigated at therapeutical concentrations at three different glucose levels (with 0, 2.22 and 5 mmol/l glucose surrounding) and in the presence of a metabolic stimulus with glucose at 8.33 mmol/l. All the sulfonylureas stimulated the B-cell function. Tolbutamide, gliquidone and gliclazide produced a prompt biphasic hormone release while glibenclamide induced a delayed monophasic insulin secretion. In all cases the amount of insulin released depended on the metabolic condition. As the environmental glucose levels fell, the sulfonylureas' stimulatory effect on the B-cell function decreased. At the therapeutical concentrations we tested, no sulfonylurea influenced A-cell activity whether directly or indirectly via an insulin-mediated paracrine inhibition of glucagon release.

[Antihypertensive efficacy of nitrendipine and its effects on carbohydrate metabolism. A controlled clinical study versus placebo]. / Efficacia anti-ipertensiva ed effetti sul metabolismo glucidico della nitrendipina. Studio clinico controllato versus placebo.

Hypertension and diabetes mellitus are both common conditions which frequently co-exist. The calcium channel blockers are potentially diabetogenic since insulin secretion may be impaired by their use. The aim of this study was to determine whether nitrendipine, a second generation dihydropyridine derivative calcium antagonist, is capable of interfering with carbohydrate metabolism and insulin secretion in hypertensive diabetics at the doses commonly used in therapy. In a 12-week double blind placebo-controlled randomized clinical trial, the effects of nitrendipine (20 mg/day) on arterial blood pressure, glycaemic homeostasis and other metabolic parameters were evaluated in 30 patients with mild to moderate essential hypertension and type II diabetes mellitus. The results showed nitrendipine to be an effective antihypertensive agent which neither impaired the overall glucose homeostasis nor caused any other potentially harmful metabolic side effect. In conclusion, these data suggest that the calcium channel antagonist nitrendipine is a metabolically safe drug to use in the treatment of hypertension, especially in patients with diabetes mellitus.

Do metformin and phenformin potentiate differently B-cell response to high glucose? An in vitro study on isolated rat pancreas.

The study investigated the effects of metformin and phenformin, at "therapeutic" concentrations, on the pancreatic A-, B- and D- cell response to glucose using the isolated perfused rat pancreas model. Changes in the rate of pancreatic lactate output after these biguanides were also evaluated. Metformin--at 1.5 micrograms/ml--and phenformin--at 100 ng/ml--were separately infused both at 160 mg/dl and 300 mg/dl glucose levels. Neither metformin nor phenformin affected glucagon or somatostatin secretion during these two metabolic stimuli with glucose, nor did they significantly influence insulin response to the lower glucose stimulus. Both metformin and phenformin enhanced insulin response to 300 mg/dl glucose infusion and increased the second phase of the B-cell secretory profile but only phenformin significantly enhanced the pancreatic lactate output rate during the 300 mg/dl glucose infusion. Infusion with dichloroacetate (a stimulator of the mitochondrial pyruvate oxidation) or with verapamil (a calcium antagonist) alone did not modify the insulin response to high glucose concentrations. During metformin infusion dichloroacetate neither modified metformin's effects on B-cell response to high glucose nor did it affect the pancreatic lactate output rate. On the other hand dichloroacetate opposed phenformin's effects on the B-cell response to high glucose and reversed the rise in the pancreatic lactate output rate. Verapamil inhibited the effect of metformin on the B-cell response to high glucose but failed to affect phenformin's influence on high-glucose induced insulin release. These data suggest both metformin and phenformin potentiate--at least in rats--the late phase of insulin secretory response to high glucose. However metformin seems to influence pancreatic B-cell activity mainly by facilitating the trans-membrane calcium ion influx responsible for the second phase of insulin release. Phenformin's influence seems indirect since it increases pancreatic lactate production which mediates the enhanced B-cell response to glucose.

Partial gastrectomy and mineral metabolism: effects on gastrin-calcitonin release.

Bone mineral metabolism was studied in 20 male patients, between 8 and 18 years, after surgical treatment for peptic ulcer (ten Billroth 1 and ten Billroth 2 gastrectomies) and in 16 sex- and aged-matched healthy controls. The bone mineral content was statistically reduced only in the Billroth 2 group. Serum 25(OH)D was lower in all patients, but fractional calcium absorption was similar to the control value. This may be due to increases in 1,25(OH)2D and parathyroid activity (particularly in Billroth 2). Serum osteocalcin levels and hydroxyproline excretion were higher than in the controls. A positive linear correlation emerged not only between serum 1,25(OH)2D and PTH levels but also between each of these and serum osteocalcin and urine hydroxyproline. Both PTH and calcitriol were inversely correlated with the bone mineral mass in Billroth 2, confirming a trend observed in Billroth 1. Although calcitonin values were normal, basal gastrin levels were severely impaired in all patients. In response to a mixed meal, increases in gastrin and calcitonin were significantly lower than in the controls. The calcitonin response to intravenous calcium and pentagastrin infusion was not significantly different to the controls. The percentage increase in gastrin and calcitonin responses to oral calcium correlated positively with the reduction in bone mineral content only in the Billroth 2 group, suggesting a reduction in calcitonin release may contribute to gastric surgery osteopenia in these patients.

Low dose metformin in the treatment of type II non-insulin-dependent diabetes: clinical and metabolic evaluations.

Low doses of metformin (500 mg twice daily) were administered to 20 diabetic patients, combined with the original sulfonylurea treatment which had become ineffective even at full dosage. After 1 and 5 weeks, the effects of the drug on glycemic control, blood intermediate metabolites and monocyte insulin receptors were monitored. Metformin clearly improved glycemic control by reducing both fasting blood glucose from 189.88 +/- 21.11 mg/dl to 131.12 +/- 16.02 mg/dl after 1 week and to 130.11 +/- 13.29 mg/dl after 5 weeks (p less than 0.025 both after 1 and 5 weeks); the diurnal blood glucose average fell from 235.33 +/- 24.11 mg/dl to 174.66 +/- 23.45 mg/dl (p less than 0.0025) after 1 week and to 177.65 +/- 21.71 mg/dl (p less than 0.0005) after 5 weeks. Consequently both blood glycosylated hemoglobin (p = n.s. after 1 week, p less than 0.025 after 5 weeks) and serum fructosamine (p less than 0.0025 after both 1 and 5 weeks) also decreased after metformin treatment. No change in plasma insulin and C-peptide levels was reported and no modification in diurnal rhythms of blood lactate, pyruvate, alanine glycerol and beta-OH-butyrate was detected at any time during metformin treatment. All the changes documented in the binding values were already complete at the end of the first week; insulin binding to monocytes increased slightly but significantly (p less than 0.05) and the number of receptors per cell rose (p less than 0.05) but could not be correlated to any index of glycemic control. These data suggest that the antidiabetic action of metformin is neither related to its lactate-increasing activity nor does it depend upon its inducing an increase in insulin binding values. This metformin-related hypoglycemic effect might be the result, at least in part, of a reduced oxidative phosphorylation without inhibition of hepatic gluconeogenesis and/or of decreased hepatic glucose output. Moreover, our data are also consistent with the hypothesis that metformin might affect insulin action at a post-receptor level.

Metformin potentiates B-cell response to high glucose: an in vitro study on isolated perfused pancreas from normal rats.

This study investigated the effects of metformin on pancreatic A-B- and D-cell functions using the isolated perfused rat pancreas model. The lactate output rate following metformin infusion was also monitored. Metformin was infused at the low "therapeutic" concentration of 1.5 micrograms/ml and its effects were evaluated in three different glycaemic conditions: during a basal infusion of 4.44 mM glucose, during a moderate increase to 8.88 mM of glucose concentration, and finally during a higher 16.66 mM glycaemic stimulus. Basal insulin secretion and B-cell release during the lower hyperglycaemic stimulus were unaffected by metformin infusion. On the contrary, the drug significantly enhanced insulin response to 16.66 mM glucose, particularly by increasing the second phase of hormone release. Glucagon and somatostatin releases during metformin infusion were similar to the secretory pattern observed in the control experiments both in the basal condition and in the presence of the two different hyperglycaemic stimuli. Finally metformin did not modify the lactate output rate from perfused pancreas, irrespective of the different glycaemic conditions employed. Therefore our data suggest--at least in rats, in in vitro experiments but above all in the presence of markedly elevated hyperglycaemic conditions--that metformin may influence the glucose stimulatory effect on B-cell activity.

[Body mass index, blood lactate and therapeutic effectiveness of metformin in type II diabetes mellitus]. / Indice di massa corporea, lattato ematico ed efficacia terapeutica della metformina nel diabete di tipo II.

Obese type II diabetic patients are often treated with metformin after full doses of sulfonylureas or insulin fail to achieve a satisfactory metabolic control. Clinical practice has often indicated that metformin has little effect on normal weight type II diabetics. The effectiveness of metformin vs placebo was evaluated in a double blind cross-over study on 53 type II diabetic patients with unsatisfactory glycaemic control. The patients were divided into two groups-the sulfonylurea-treated (S) and the insulin treated (I). Each group was then subdivided into three classes: 1) normal weight [BMI less than 25], 2) overweight [BMI 25-30] and 3) obese [BMI greater than 30]. Metformin did not modify body weight, plasma lipids or insulin profiles. Blood lactate increased slightly but only occasionally reached statistical significance. Metformin's antidiabetic activity was not influenced by the basal treatment (S or I) of the diabetics but was strongly linked to the degree of adiposity. Indeed both plasma glucose and HbA1 remained almost unchanged in normal weight patients. In the overweight and in the obese metformin significantly improved glycaemic profiles and reduced HbA1 levels. These results confirm clinical experience indicating that some degree of adiposity is a necessary prerequisite for metformin efficacy in diabetics.

Effects of long-term glibenclamide administration on gastrointestinal and pancreatic hormones in normal fasting rats.

We previously reported that sulfonylurea treatment reduces insulin (IRI), glucagon (IRG) and somatostatin (SRIF) release following metabolic stimuli from the isolated perfused pancreas of normal rats and that a reduction in IRI, IRG and SRIF pancreatic content was also observed. The present work was undertaken to investigate the effects of long-term glibenclamide treatment on the gastrointestinal content of gut hormones in normal rats. Moreover, the effects of sulfonylurea treatment on IRI, IRG, and SRIF pancreatic content were also analyzed and compared to the peripheral hormone plasma levels. Two groups of male Sprague-Dawley rats received glibenclamide (1 mg/kg/day per os; n = 14) or placebo (distilled water; n = 10) for 5 months, respectively. Tissue contents of IRI, IRG and SRIF in acid-ethanol extracts of pancreas and of gastric inhibitory peptide (GIP), vasoactive intestinal polypeptide (VIP), entero-glucagon (gut-GLI) and SRIF in acid-ethanol extracts of intestine were determined. Blood glucose and plasma pancreatic hormone levels were also measured. Glibenclamide treatment lowered the levels of IRI, IRG and SRIF in the pancreatic tissue; in the same way gut-GLI, SRIF and VIP intestinal concentrations were significantly reduced, whereas no significant inhibition was detected in intestinal GIP content. Blood glucose levels and IRI and SRIF plasma concentrations were similar in the two groups. IRG plasma levels were reduced in the sulfonylurea group. These findings might suggest that sulfonylurea suppresses hormone biosynthesis in a non-specific manner.

Pancreatic A- and D-cell response to arginine during acute alloxan-induced intra-islet insulinopenia.

This study was performed to investigate the role of pancreatic B-cell function on glucagon and somatostatin response to arginine. Isolated perfused rat pancreas was used for the experiment. Acute B-cell destruction was induced in vitro by 0.56 mM alloxan infused directly into the vascular system of the perfused pancreas. This resulted in a fall in basal insulin release and in a complete absence of hormone response to 20 mM arginine. Glucagon and somatostatin release during metabolic stimulus was superimposable on that observed in the control experiments (no alloxan infusion). We conclude that a normal B-cell function is not required for glucagon and somatostatin response to arginine.

Selective impairment of pancreatic A cell suppression by glucose during acute alloxan-induced insulinopenia: in vitro study on isolated perfused rat pancreas.

This study was performed in order to investigate the role of insulin in the modulation of pancreatic A cell response to glucose. The isolated perfused rat pancreas model was used: intraislet insulinopenia was induced in vitro by 0.56 mM alloxan infusion over 15 min. Alloxan caused a transitory insulin release but did not affect glucagon secretion. Exposure to alloxan completely abolished insulin response to 20 mM arginine, 1.6 mM glucose, and 11.1 mM glucose. Glucagon response to 20 mM arginine and 1.6 mM glucose was unchanged by alloxan pretreatment compared to control pancreata not treated with alloxan. However, the suppression of glucagon release by 11.1 mM glucose was abolished in the alloxan experiments. Twenty milliunits per ml of insulin infused during 11.1 mM glucose infusion restored glycemic suppression of glucagon release, but it produced only a slight inhibitory effect on A cell function in the presence of 3.9 mM glucose. Our study indicates that glucose is the physiological suppressor of the pancreatic A cell and that, in this regard, insulin exerts only a permissive effect.