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Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.

Aims/hypothesis: Loss of the trophic support provided by surrounding non-endocrine pancreatic cell populations underlies the decline in beta cell mass and insulin secretory function observed in human islets following isolation and culture. This study sought to determine whether restoration of regulatory influences mediated by ductal epithelial cells promotes sustained beta cell function in vitro., Methods: Human islets were isolated according to existing protocols. Ductal epithelial cells were harvested from the exocrine tissue remaining after islet isolation, expanded in monolayer culture and characterised using fluorescence immunocytochemistry. The two cell types were co-cultured under conventional static culture conditions or within a rotational cell culture system. The effect of co-culture on islet structural integrity, beta cell mass and insulin secretory capacity was observed for 10 days following isolation., Results: Human islets maintained under conventional culture conditions exhibited a characteristic loss in structural integrity and functional viability as indicated by a diminution of glucose responsiveness. By contrast, co-culture of islets with ductal epithelial cells led to preserved islet morphology and sustained beta cell function, most evident in co-cultures held within the rotational cell culture system, which showed a significantly (p < 0.05) greater insulin secretory response to elevated glucose compared with control islets. Similarly, insulin/protein ratio data suggested that the presence of ductal epithelial cells is beneficial for the maintenance of beta cell mass., Conclusions/interpretation: The data indicate a supportive role for ductal epithelial cells in islet viability. Further characterisation of the regulatory influences may lead to novel strategies to improve long-term beta cell function both in vitro and following islet transplantation.

Background: Gefitinib (IRESSA) is normally administered as a once-daily oral tablet. However, many patients with head and neck cancer have difficulty swallowing medication in a tablet form. A granular formulation has recently been developed to facilitate the administration of gefitinib to patients who are unable to swallow tablets., Objectives: The aims of this study were to determine the relative bioavailability of a single dose of gefitinib when administered as 250 mg of a new granular formulation compared with the standard 250 mg tablet, and to assess the intra-subject variability of the granular formulation, in healthy subjects., Methods: This was a randomized, open-label, three-period crossover study. Healthy male subjects (n = 18) received either a single gefitinib 250 mg tablet (once), or a 250 mg granular formulation of gefitinib (on two separate occasions) over the three dosing periods, in randomized order. Plasma concentrations of gefitinib were measured up to 240 h post-dose., Results: The treatment ratio estimates for area under the plasma concentration versus time curve (AUC) and peak plasma concentration (C (max)) for the granular formulation when compared with the tablet were 1.05 (90% confidence intervals [CI] for the ratio 0.97-1.13) and 1.14 (90% CI for the ratio 1.01-1.28), respectively. The estimate for the intra-subject standard deviation for the granular formulation when given on 2 separate occasions was 0.143 for AUC and 0.165 for C (max), equivalent to a 1.4- and 1.7-fold intra-subject variability in AUC and C (max), compared with that observed for the tablet of two and threefold, respectively., Conclusions: There was little difference in exposure to gefitinib administered as the 250 mg granular formulation compared with the 250 mg standard tablet. The granular formulation of gefitinib could provide an alternative treatment regimen for patients unable or unwilling to swallow the standard tablet formulation, without compromizing exposure to gefitinib.

Objectives: To determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy volunteers., Methods: An open-label, single-center, phase I study in healthy male volunteers. Each volunteer received a single 250 mg oral dose of gefitinib on day 1. On days 11-14, oral loading doses of 60 mg tamoxifen were administered, followed by 20 mg tamoxifen for a further 16 days to maintain steady-state exposure. On day 24, volunteers received a second single 250 mg oral dose of gefitinib. The last dose of tamoxifen was given on day 30. Pharmacokinetic and safety assessments were conducted throughout the trial., Results: A total of 18 volunteers were recruited. The presence of tamoxifen did not have a clinically significant effect on the primary variables AUC and Cmax of gefitinib, nor on the secondary variables AUC(0-t), tmax, t1/2, and lambdaz. The geometric least square mean values for AUC were 3,407.6 versus 3,397.9 ng.h/ml in the absence and presence of tamoxifen, respectively (90% CL 0.894, 1.112) and for Cmax were 110.8 versus 103.6 ng/ml, respectively (90% CL 0.786, 1.111). The combination of gefitinib with tamoxifen was generally well tolerated by the volunteers. There were no serious adverse events and no volunteer discontinued the study due to an adverse event. NCI-CTC grade 1/2 drug-related adverse events were observed in seven volunteers, including loose stools and skin events associated with gefitinib, and lethargy and headache, flushing, and dizziness associated with tamoxifen., Conclusions: This study suggests that tamoxifen has no significant effect on the pharmacokinetics, tolerability, or safety of a single 250 mg oral dose of gefitinib. Therefore, in clinical investigations of this combination, no dose adjustment of gefitinib is indicated.

Aims/hypothesis: This study examined the plasma stability, biological activity and antidiabetic potential of two novel N-terminally modified analogues of gastric inhibitory polypeptide (GIP)., Methods: Degradation studies were carried out on GIP, N-acetyl-GIP (Ac-GIP) and N-pyroglutamyl-GIP (pGlu-GIP) in vitro following incubation with either dipeptidylpeptidase IV or human plasma. Cyclic adenosine 3'5' monophosphate (cAMP) production was assessed in Chinese hamster lung fibroblast cells transfected with the human GIP receptor. Insulin-releasing ability was assessed in vitro in BRIN-BD11 cells and in obese diabetic ( ob/ ob) mice., Results: GIP was rapidly degraded by dipeptidylpeptidase IV and plasma (t(1/2) 2.3 and 6.2 h, respectively) whereas Ac-GIP and pGlu-GIP remained intact even after 24 h. Both Ac-GIP and pGlu-GIP were extremely potent ( p<0.001) at stimulating cAMP production (EC(50) values 1.9 and 2.7 nmol/l, respectively), almost a tenfold increase compared to native GIP (18.2 nmol/l). Both Ac-GIP and pGlu-GIP (10(-13)-10(-8) mmol/l) were more potent at stimulating insulin release compared to the native GIP ( p<0.001), with 1.3-fold and 1.2-fold increases observed at 10(-8) mol/l, respectively. Administration of GIP analogues (25 nmol/kg body weight, i.p.) together with glucose (18 mmol/kg) in ( ob/ ob) mice lowered ( p<0.001) individual glucose values at 60 min together with the areas under the curve for glucose compared to native GIP. This antihyperglycaemic effect was coupled to a raised ( p<0.001) and more prolonged insulin response after administration of Ac-GIP and pGlu-GIP (AUC, 644+/-54 and 576+/-51 ng.ml(-1) x min, respectively) compared with native GIP (AUC, 257+/-29 ng.ml(-1) x min)., Conclusion/interpretation: Ac-GIP and pGlu-GIP, show resistance to plasma dipeptidylpeptidase IV degradation, resulting in enhanced biological activity and improved antidiabetic potential in vivo, raising the possibility of their use in therapy of Type II (non-insulin-dependent) diabetes mellitus.

The effects on glucose homeostasis of eleven plants used as traditional treatments for diabetes mellitus were evaluated in normal and streptozotocin diabetic mice. Dried leaves of agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra) were studied. Each plant material was supplied in the diet (6.25% by weight) and some plants were additionally supplied as decoctions or infusions (1 g/400 ml) in place of drinking water to coincide with the traditional method of preparation. Food and fluid intake, body weight gain, plasma glucose and insulin concentrations in normal mice were not altered by 12 days of treatment with any of the plants. After administration of streptozotocin (200 mg/kg i.p.) on day 12 the development of hyperphagia, polydipsia, body weight loss, hyperglycaemia and hypoinsulinaemia were not affected by blackberry, celandine, lady's mantle or lily of the valley. Garlic and liquorice reduced the hyperphagia and polydipsia but did not significantly alter the hyperglycaemia or hypoinsulinaemia. Treatment with agrimony, alfalfa, coriander, eucalyptus and juniper reduced the level of hyperglycaemia during the development of streptozotocin diabetes. This was associated with reduced polydipsia (except coriander) and a reduced rate of body weight loss (except agrimony). Alfalfa initially countered the hypoinsulinaemic effect of streptozotocin, but the other treatments did not affect the fall in plasma insulin. The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice.

The role of ovarian hormones in the long-term control of B-cell function of in the mouse has been examined. Ovariectomised adult female mice were treated with daily subcutaneous replacement doses of oestradiol (5 microgram/kg), progesterone (1 mg/kg), both hormones combined, or vehicle only for 15 weeks. Ovariectomy caused a 40% increase in plasma glucose concentrations during glucose tolerance tests, a 26% decrease in the plasma insulin response to glucose (2 g/kg IP) and a 32% decrease in the plasma insulin response to arginine (2 g/kg IP) compared with control mice. When islets from ovariectomised mice were incubated for 30 minutes in media containing 28 mmol/l glucose or 2.8 mmol/l glucose with 5 mmol/l arginine, insulin release was reduced by 23% and 31% respectively. Total pancreatic and islet insulin content were each decreased by 36%, and the number of B-cells was decreased by 39% in the ovarietomised mice. These detrimental effects of ovariectomy were partially or totally prevented by the oestradiol and progesterone treatments. The results indicate that ovarian oestrogens and progestogens may play an important role in the long-term maintenance of B-cell competence in the female mouse.

The effect of metformin on hepatocyte insulin receptor binding was examined in normal, streptozotocin diabetic and genetically obese diabetic (ob/ob) mice. In normal mice, chronic administration of metformin (60 mg X kg-1 X day-1 for 50 weeks) increased the number of low affinity receptors by 148%. During acute studies, metformin increased (30%) the number of low affinity receptors after 24 h. When metformin was withdrawn after treatment for 96 h, the number of low affinity receptors decreased, approaching control values by 48 h. In severely insulin resistant ob/ob mice, the concentrations of high and low affinity receptors were reduced by 60% and 27%, respectively. A high dose of metformin (240 mg X kg-1 X day-1 for 4 weeks) increased the concentration of high and low affinity receptors in ob/ob mice by 63% and 86%, respectively. However, the hypoglycaemic response to exogenous insulin was not altered. In streptozotocin-diabetic mice, the number of low affinity receptors was increased by 68% compared with normal mice. Metformin (60 mg X kg-1 X day-1 for 10 weeks) did not significantly alter the number of insulin receptors in streptozotocin-diabetic mice, but the hypoglycaemic response to exogenous insulin was improved by 94%. The results raise the possibility that metformin might affect post-receptor sites of insulin action independently of effects at the receptor level.

To investigate the effect of the ob gene in the heterozygous condition, plasma glucose and insulin responses of adult heterozygous lean (ob/+) mice were compared with mice of the homozygous lean (+/+) and homozygous obese (ob/ob) genotypes. The ob/+ mice consumed 24% more food than +/+ mice although body weights were similar. Plasma glucose and insulin concentrations were respectively 16% and 176% higher in ob/+ mice than +/+ mice in the freely fed state, and 44% and 88% higher during glucose tolerance tests. In 24 hour fasted ob/+ mice, plasma glucose concentrations were 23% higher than +/+ mice but plasma insulin concentrations were not significantly different. Arginine produced a greater insulin response (172%) and a greater fall in glycaemia (200%) in ob/+ mice. A significant difference in the hypoglycaemic effect of insulin in ob/+ and +/+ mice was not observed. These results demonstrate an effect of the ob gene on glucose homeostasis in heterozygous lean (ob/+) mice. The abnormalities were qualitatively similar but considerably less severe than those in ob/ob mice, suggesting that ob/+ mice might prove useful to study factors predisposing to inappropriate hyperglycaemia.

Plasma glucose and insulin responses to opiate receptor stimulation and antagonism were determined in 12-14 week old lean and obese-diabetic Aston ob/ob mice. The opiate receptor antagonist naloxone (1 mg/kg intraperitoneally) rapidly and transiently raised glucose and suppressed insulin concentrations in lean mice, and produced qualitatively similar but more protracted response in ob/ob mice. Selective stimulation of mu- and delta-opiate receptors using the enkephalin analogues Tyr-D-Ala-Gly-MePhe-NH(CH2)2OH (1 mg/kg, intraperitoneally) and Tyr-D-Ala-Gly-Phe-D-Leu (10 mg/kg intraperitoneally) respectively, rapidly and transiently increased glucose and insulin concentrations in lean and ob/ob mice. The ob/ob mice exhibited greater glucose and insulin responses to these analogues. The results provide evidence that endogenous opiates participate in the regulation of glucose and insulin homeostasis, and suggest that increased responsiveness to mu- and delta-opiate receptor stimulation may contribute to the hyperglycaemia and hyperinsulinaemia of obese-diabetic mice.

The rapid growth (0.8 +/- 0.3 g/day) of a transplantable insulinoma, which also contained substance P (2.9 +/- 2.3 pmol/g) and gastrin-releasing peptide (3.2 +/- 2.1 pmol/g), resulted in the development of hyperphagia, hyperinsulinaemia and hypoglycaemia in rats (n = 8). After a 14-day growth period, the insulinoma-bearing rats showed an increase (49%; p less than 0.01) in the weight of the small intestine but no significant change in stomach weight compared with control animals. The content (pmol/organ) of somatostatin, substance P, neurokinin A and vasoactive intestinal peptide in the stomachs of the tumour rats was unchanged. A depletion in the content (53% p less than 0.01) and concentration (57%; p less than 0.01) of gastrin-releasing peptide, however, suggested either hypersecretion, possibly mediated through hypoglycaemia-induced vagal stimulation, or inhibition of synthesis. The concentration and content of glucagon-like immunoreactivity (enteroglucagon) in the small intestine of the insulinoma rats increased markedly (47%; p less than 0.01 and 120%; p less than 0.01). This increase is consistent with a proposed role of this peptide as a factor trophic to the intestinal mucosa. No significant changes in the concentrations of somatostatin, substance P, neurokinin A, vasoactive intestinal peptide and gastrin-releasing peptide in the small intestine were observed. However, the increase in gut weight resulted in a greater content of vasoactive intestinal peptide (40%; p less than 0.01) and substance P (37%; p less than 0.05) in the insulinoma rats.