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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.

The authors describe the diurnal profile of plasma metformin concentrations in a group of 6 Type 2 (noninsulin-dependent) diabetic patients studied at two different daily metformin doses (500 mg and 850 mg b.d.) and report data on the relationships between plasma metformin and metabolic effects over a 14 h period. In addition, the effect of circulating metformin on insulin binding to isolated monocytes has been evaluated. At the two different daily doses fasting plasma metformin concentrations were similar (3.23 +/- 0.35 mumol/l and 3.86 +/- 0.72 mumol/l, mean values +/- SEM, at low and high dose respectively). Drug peak values and averaged concentrations (4.66 +/- 0.39 mumol/l vs 6.35 +/- 0.69 mumol/l) were significantly higher when more drug was administered. Mean plasma glucose was lower when 1,700 mg/day instead of 1,000 mg/day of metformin was given (7.3 +/- 0.4 mmol/l vs 9.1 +/- 0.9 mmol/l, p less than 0.05). After dosing, at higher plasma metformin concentrations corresponded lower plasma glucose values. The averaged blood lactate levels resulted 1.46 +/- 0.4 mmol/l (p less than 0.05 vs matched diet treated diabetic patients) at the higher drug dose. A significant positive correlation emerged between mean plasma metformin concentrations and mean blood lactate levels (r: 0.76, p less than 0.02). Alanine, glycerol and B-OH-butyrate levels were similar at the two metformin daily doses, and were not correlated to plasma metformin. The binding of insulin to isolated human monocytes was similar in metformin-treated diabetic patients (4.48 +/- 0.45) as in healthy volunteers (4.62 +/- 0.34); insulin binding was correlated (p less than 0.05) with plasma metformin levels.

Twelve outpatients with type II diabetes mellitus and mild clinical signs and history of cardiac failure were studied to assess the effects of ibopamine on glucose and lipid metabolism. For the assessment of cardiac failure a clinical score was computed, based on the evidence of dyspnea and ankle oedema. The patients were randomly allocated to ibopamine 100 mg t.i.d. or placebo in a double-blind cross-over 3 weeks design. Daily plasma glucose profile, glycaemia and plasma insulin during glucose tolerance test, serum C-peptide, lactacidemia, free fatty acids, triglycerides, urinary glucose, diuresis and clinical evaluation were the studied parameters. During the study, a clinically favourable trend for ibopamine was observed, as far as cardiac failure was concerned. No significant differences were found between ibopamine and placebo in any of the metabolic parameters. No change in diet or in the previous dosage of the antidiabetic drugs occurred during the study in any patient. We conclude that ibopamine 100 mg t.i.d. does not affect metabolic control and lipid pattern in type II diabetic patients, therefore representing a safe tool for the treatment of chronic heart failure in these patients.

Salivary immunoreactive insulin was measured in 45 insulin-treated diabetic patients directly from saliva samples by a radioimmunoassay procedure. Mean and median fasting salivary immunoreactive insulin was respectively 88.5 and 54.0 pmol/L (range 12.2-633.6 pmol/L); fasting salivary insulin values were positively correlated with steady-state plasma free-insulin levels measured in immediately extracted plasma samples (r = 0.62, p less than 0.001) and with daily insulin dose (r = 0.32, p less than 0.05). After subcutaneous injection of 15 U regular insulin in 6 type 1 diabetic patients, salivary insulin concentrations increase reflected that of plasma free-insulin during a 6 h period although with a 60 min time lag. Mean salivary insulin values and plasma free-insulin concentrations were significantly correlated to each other both at each time point (p less than 0.001) and when the mean salivary insulin levels were plotted against the mean plasma free-insulin values 60 min earlier (p less than 0.001). These results suggest that the measurement of salivary immunoreactive insulin (that is easier, faster and cheaper than plasma free-insulin assay) may be usefully employed as an approximation of plasma free-insulin concentrations for clinical and research purposes in patients with circulating anti-insulin antibodies.