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Gen Pharmacol. 2000 Mar;34(3):183-91.
Effect of acute and sub-chronic administration of the imidazoline compound S 22068 on in vivo glucose and insulin responses in normal lean CBA/Ca mice.

Williams CA, Shih MF, Taberner PV.

Department of Pharmacology, School of Medical Sciences, University of Bristol, University Walk, BS8 1TD, Bristol, UK.

Acute S 22068 (24 mg/kg po) improved glucose tolerance and increased insulin sensitivity, assessed as the acute blood glucose response to exogenous insulin. The same acute dose did not stimulate insulin secretion or induce hypoglycemia in fed animals. Comparison of acute S 22068 to equipotent doses (with respect to effect on glucose tolerance) of gliclazide (2 mg/kg) and metformin (60 mg/kg) found S 22068 to be similar to metformin with respect to its effects on basal glucose levels (BGL) and insulin sensitivity. This also suggests that S 22068 acts by a mechanism which does not involve insulin release. Acute or sub-chronic S 22068 (14 days at 25 mg/day) had no effect on brown adipose tissue (BAT) or white adipose tissue (WAT) lipogenesis, an insulin-sensitive metabolic pathway. Sub-chronic treatment with S 22068 did not alter body weight (BW) or food intake, and resulted in tolerance to its effects on glucose metabolism and insulin sensitivity. These findings suggest that S 22068 is similar in effect to metformin, and is not insulinogenic, in contrast to the sulfonylureas or putative I(3) imidazoline site ligands.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11120380&dopt=Abstract

chu-montpellier.fr

OBJECTIVE: To compare substrates oxidative patterns in type 2 diabetic patients treated with sulphonylurea alone or in combination with metformin. METHODS: Plasma glucose (PG), plasma insulin (PI) and substrates oxidation rates measured by indirect calorimetry were compared during a test day at 8.00 a.m. (before breakfast), 11.00 a.m. (before the lunch), 2.00 p.m. (2 h after the lunch) and at 5.00 p.m. in 56 diabetic patients treated with diet (group C, n = 14), sulphonylurea (group S, n = 14) or with a sulphonylurea-metformin combination (group SM, n = 28). RESULTS: The three groups were comparable for age, body mass index (b.m.i.), body composition and PG levels. Mean glucose oxidation (Gox) was increased since mean lipid oxidation (Lox) was decreased in group S in comparison both with group C (3.02+/-0.08 vs. 2.62+/-0.08 g/min/kg/10(3), p < 0.05; 0.53+/-0.04 vs. 0.88+/-0.09 g/min/kg/10(3), p < 0.01). Mean Lox was also decreased in group S in comparison with group SM (0.88+/-0.06 vs. 0.53+/-0.04 g/min1/kg1/10(3), p < 0.0001) whereas the difference in Gox between these latter two groups was only significant in the basal state (1.94+/-0.17 vs. 2.47+/-0.17 g/min1/kg1/10(3), p < 0.05). Mean respiratory quotient (RQ) was increased in group S (0.90+/-0.01) in comparison both with group C (0.86+/-0.01, p < 0.001) and with group SM (0.86+/-0.01, p < 0.001). Mean energy expenditure was lower in group S than in group SM (21.4+/-0.6 vs. 23.6+/-0.6 kcal/min/kg/10(3), p < 0.05). Substrates oxidative patterns, RQ values and energy expenditure were similar in group C and in group SM. CONCLUSIONS: When compared to patients treated with a sulphonylurea-metformin bitherapy, patients treated with a sulphonylurea monotherapy have a shift in their ratio of fat to carbohydrate oxidation that could make body weight loss more difficult in this latter group.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11225656&dopt=Abstract

sint.azm.nl

OBJECTIVE: To assess which factors influence or predict the efficacy of insulin therapy in subjects with type 2 diabetes, who were poorly controlled despite maximal doses of oral glucose lowering agents. RESEARCH DESIGN AND METHODS: Seventy-five patients with type 2 diabetes participated (mean age (+/- SD), 67 +/- 8 years; body mass index, 25.8 +/- 5.0 kg/m2; median time since diagnosis of diabetes, 8 years (range 1-36); 27 males and 48 females). They were transferred to insulin therapy, in which case either insulin alone, or a combination of insulin and glibenclamide was employed. The importance of baseline parameters (glycaemic control, beta-cell function, measures of insulin resistance) was assessed by comparing good and poor responders (defined as achieved HbA1c < 8.0 or > 9.0%) to insulin therapy, and by multiple logistic regression analysis of these baseline parameters and achieved metabolic control. RESULTS: During insulin therapy, HbA1c levels decreased from 10.9 +/- 1.3 to 8.2 +/- 1.1% (p < 0.001), and fasting blood glucose levels decreased from 14.0 +/- 2.3 to 8.2 +/- 2.1 mmol/l (p < 0.001). Thirty patients reached HbA1c levels < 8.0%, 21 of them even < 7.5%. The mean increase in body weight was 4.5 kg. HbA1c after 6 months was 7.0 +/- 0.6% in the good responders, and 9.8 +/- 0.6% in the poor responders (p < 0.001), despite a comparable insulin dose. Baseline metabolic control was similar in both groups. Also, glucagon-stimulated and calculated insulin secretion, as well as parameters of insulin resistance, such as fasting serum insulin levels, free fatty acids, and serum triglycerides, were not different between both groups, and certainly not higher in the poor responders. Also previous metformin use was not different. However, poor responders were more obese than good responders, and had significantly longer known duration of diabetes. Multiple logistic regression confirmed that only duration of diabetes and body mass index were independent predictors of response to insulin therapy. CONCLUSIONS: We conclude that in elderly patients with type 2 diabetes improvement of glycaemic control can be achieved at the expense of some weight gain. Measurement of residual insulin secretion prior to institution of insulin treatment does not discriminate between good and poor responders to this model of therapy. Especially in obese patients with longer duration of diabetes more attention is needed in order to achieve optimal glycaemic control. Combination of insulin with newer drugs, like thiazolidinediones, may perhaps achieve this.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10079680&dopt=Abstract












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