- Email: [email protected]
No reactive hypoglycemia in type 2 diabetic patients after subcutaneous administration of GLP-1 and I.V. glucose
Track 2. Clinical Research & Care phase II study aimed to demonstrate improvement in overall metabolic control. M a t e r i a l and Methods: A multicenter, double-blind study which randomized 385 patients with Type 2 diabetes mellitus (T2DM) inadequately controlled on glibenclamide (G) alone to 15mg G in combination with either placebo (P) or one of 6 daily doses of GI262570 (0.25, 0.5, 1, 2, 5, or 10mg) for 12 weeks. Results: Mean baseline HbAlc and fasting serum glucose (FSG) values following a 4- week stability period on 15mg G are listed in the table below. After 12 weeks of combination treatment, the 1-10mg dose groups resulted in significant decreases in FSG and H b A l c vs. P (see table). Adding G1262570 to G treatment led to significant FSG falls within 2-4 weeks. Categorical response assessments vs. G alone treatment baseline values demonstrated that over 85% of subjects achieved FSG lowering of >- 1.67 mmol/L and H b A l c decreases of >-0.7% by 12 weeks for the 5mg or 10mg doses. As with other PPARy agonists, dose-related weight gain, peripheral oedema, and decreases in haemoglobin were observed in the GI262570 + G treatment groups. The incidence of hypoglycaemic symptoms was increased in the G + 10mg GI262570 group. Parameter
G+P
G+I
G+2
G+5
G+I0
Numberof subjects(Intent-to-Treat) Baseline(B) FSG (retool/L) FSG A vs. P at 12 weeks % of subjects>- 1.67 mmol/LFSG A vs. B BaselineHbAlc(%) HbAlc A vs. P at 12 weeks % of subjects>_-0.7% HbAlc A vs. B
56 13.7 31% 9.7 22%
53 14.1 -2.0+ 54%# 9.8 -0.7+ 50%*
48 13.7 -1.7" 53%# 9.6 -0.5# 38%
54 13.9 -4.7+ 87%+ 10.0 -1.9+ 87%+
52 14.5 -5.4+ 90%+ 9.7 -2.1+ 92%+
Significancelevelsvs. P: # = p < 0.05 * = p < 0.005 + = p < 0.001
Conclusions: Overall, GI262570 in combination with sulfonylurea significantly improves metabolic control in the treatment of T2DM.
P232 The GLP-1 Analogue, LY307161, Potently Lowers Post Prandial Blood Glucose in Subjects with Type 2 Diabetes STEVEN J. PASCOE, Christopher Payne, Michael Trautmann. Clinical Pharmacology, Eli Lilly & Company, Erl Wood Manor, Windlesham, United Kingdom Glucagon-like peptide 1 (GLP-1) is a potent antidiabetic agent acting through stimulation of insulin release, suppressing glucagon levels, and inhibiting gastric emptying. Despite the effectiveness in patients with type 2 diabetes GLP-1 itself is unsuitable for therapeutic use due to its short biological half life. We have developed a degradation-resistant analogue LY307161with longer duration of action. The aim of this study was to examine the effects of single doses of LY307161 on glucose, insulin and glucagon in subjects with type 2 diabetes following a standardised high carbohydrate meal. 20 patients (14 males, age 60.3+1.5 yrs., BM128.3+0.8 kg/m2, duration of diabetes 1.5-18 yrs.) participated after a 7 day washout period from their previous antidiabetic medications. Each subject was dosed with placebo and 3 doses of LY307161 from the following doses, 30/~g, 100/zg, 180/zg, 300/zg, 450#g. Each dose was administered to twelve subjects. LY307161 was administered subcutaneously just prior to the consumption of a standardised meal. Blood was taken at 0, 30, 60, 120, 240 and 300 minutes post dose for glucose, insulin and glucagon assays. The high postprandial rise in blood sugar seen with placebo was attenuated in a dose dependent manner by all doses of LY307161. The maximum difference from placebo was seen at 2 hours post dosing, lasting for up to 4 hours. Compared to placebo glucose was 9.58 mmol/l lower after the 450/zg dose. Insulin levels showed an initial elevation for less than 1 hour, proportional to dose. Glucagon was suppressed for 2-4 hours showing a temporal correlation with glucose suppression. There was no evidence of any later rebound increase in glucose levels. Despite the potent lowering of glucose no hypoglycemic episodes occurred. In conclusion, LY307161
$41
demonstrated a potent effect on post prandial glucose levels in subjects with type 2 diabetes. The lowering of glucose levels was of both sufficient magnitude and duration to suggest that LY307161 could be a useful therapeutic agent in the treatment of type 2 diabetes. Furthermore the time course of the insulin and glucagon responses suggest that the role of glucagon in mediating the effects of GLP- 1 may have been underestimated.
P233 LY307161, a Giucagon Like Peptide (GLP-1) Analogue with Prolonged Action, Does Not Cause Hypoglycaemia STEVEN J. PASCOE, Christopher Payne, Eiry Roberts, Michael Trautmann. Clinical Pharmacology, Eli Lilly & Company, Erl
Wood Manor, Windlesham, United Kingdom GLP-1 is an effective and strictly glucose dependent insulin secretagogue. Since clinical use of GLP-1 is limited by the extremely short half life we have developed a longer acting analogue, LY307161. In this study we examined the effect of single doses of LY307161 on blood glucose in fasted healthy subjects over a wide range of doses. Twenty four healthy subjects were given placebo, and 3 doses of LY307161 from the following dosing levels, 5#g, 10/zg, 20/zg, 40/zg, 80p.g, 160/~g, 320/zg, 400#g, 500#g, 700/zg, 900/zg. Six subjects received each dose. LY307161 was administered by subcutaneous injection, after an overnight fast. Blood samples were taken at 0, 30, 60, 120, 240 minutes after injection for blood glucose determination. During this period no food intake was permitted. Subjects showed a dose dependent fall in blood glucose compared to placebo, which was maximal at 30 minutes and had returned to baseline at 120 minutes. The maximal fall, from baseline, for any dosing group was 33 mg/dL. The fall plateaued at a dose of 500#g. No further increase was seen with higher doses. The mean maximal fall seen at any dose was to an absolute level of 47 mg/dL and no subject experienced any symptoms of hypoglycaemia. In conclusion, LY307161 exhibited a duration of action greater than that previously demonstrated with natural GLP-1. The response proved glucose dependent and even high doses were unable to induce hypoglycaemia, in keeping with the known effects of GLP- 1.
P234 No Reactive Hypoglycemia in Type 2 Diabetic Patients after Subcutaneous Administration of GLP-1 and I.V. Glucose TINA VILSBOLL, Thure Krarup, Sten Madsbad, Jens J. Holst. Dept. of Internal Medicne E Gentofte Hospital; Dept. of Medical Physiology, The Panum Institute; Dept. of Endocrinology, Hvidovre Hospital, Copenhagen, Denmark It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide 1 (GLP-I) concomitant with i.v. glucose results in reactive hypoglycemia in healthy subjects. Since GLP-1 is also effective in type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-I can cause hypoglycemia in such patients. Eight type 2 diabetic patients (age: 54(49-67) years; BMI: 31(27-38) kg/m2; HbAlc: 9.4(7.0-12.5)% and 7 matched healthy subjects (HbAic: 5.5(5.2-5.8)%, FPG: 5.4(5.0-5.7) mmol/1) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 minutes later, plasma glucose (PG) was raised to 15 mmol/l with an i.v. glucose bolus. Hypoglycemia with a PG at or below 2.5 mmol/l was seen in 5 of the 7 healthy subjects after 60-70 min, but PG spontaneously increased again, reaching 3.7 (3.3-4.0) mmol/l at 90 min. In the type 2 diabetic patients, PG fell slowly and stabilized at 8.6 (4.2-12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (p<0.02).
$42
Poster Session 1
Conclusion: Subcutaneous GLP-1 plus i.v. glucose induced reactive hypoglycemia in healthy subjects, but not in type 2 diabetic patients. Therefore, a GLP-1 based therapy would not be expected to be associated with an increased risk of hypoglycemia in type 2 diabetes mellitus.
P235 Antidiabetic Effect of Neoflavonoid Coutareagenin in STZ Diabetic Rats and Diabetic Menopausal Women R. KOREC j, M. Korecovfi 2, K.H. Sensch 3, T. Zoukas 3. J Diabetes Res Lab.Med.Fac.Univ., Ko~ice; 2 IDF President W.Mayes Jr.Diabet.Dept., Tren6fn, Slovakia (Slovak Republic); 3 Gehrlicher Labor, Eurasburg, Germany Extracts from the bark of southamerican Hintonia/Couterea/latiflora are used by indigenous people as antidiabetic agent and in Germany its alcoholic extract Sucontral-R for decades by people with mild diabetes. The first author has proven that Sucontral R depressed in dosis 100 or 200mg/kg after gavage/IG/in wakeful STZ-diabetic rats of both gender hyperglycemia of 21 up to 29 mmol/l by 32 up to 42% after 2 and 4h, and this dosis administered in drinking water depressed hyperglycemia from 19 to 13mmol after one-two days. Zoukas synthetized the active substance of Sucontral, CoutareagenirdCTR/, a neoflavonoid, which dissolved in Propylen/PRG/or Polyethylen-glycol/PEG/, administered IG in dose 3, 6, 9 and 18mg/kg to 208 STZ chronically diabetic rats, with initial glycemia ranging between 20 and 39mmol/l, depressed it by 21 up to 29%, even after 14h of fasting. CTR dissolved in PRG or PEG, in dose lmg/kg IV, depressed in further 94 rats hyperglycemia of 24 up to 26mmol/l by 25 up to 35%, in which tolbutamide/60mg&g IV/, highly effective in non-diabetic rats, caused a decrease by 7% only. Because after repeated oral, IG, IV administration of Sucontral or CTR in rats no toxic symptoms were observed, eight instructed, complying postmenopausal diabetic women, not well compensated by diet or sulphonylureas, with mean age 56.6 and 9.3y of diabetes duration, took daily before three meals 2ml of Sucontral for 3 up to 12 months. After three months already, their initial fasting glycemia fell from 114-1.9/+SD/to 8.4q-lmmol, and their postprandial glycemia from 154-1.8 to 1 lq-l/p < 0.057 and HbAlc from 94-0.96 to 8.34-1.2, without changes in hepatic ALT, GMT and ALP. Moreover, patients reported feelings of well-being, disappearance of disagreable vegetative symptoms as sweating in the upper part of their body, of fatigue, anorhexia and dyspepsia. Conclusion: After proving the hyperglycemia depressing effectivity of Sucontral and of its active principle neoflavonoid Coutareagenin in 336 STZ. diabetic, tolbutemide resistant rats, without any signs of toxicity, authors document its antidiabefic activity also in postmenopausal diabetic women with additional beneficial effects on their vegetative symptoms.
P236 Subcutaneous Exendin-4 Improves 24 Hour Glucose Exposure in Type 2 Diabetes H. MAKSOUD, B.A. Barrow, S.E. Manley, J.C. Levy. Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, United Kingdom Exendin-4 (E) is a 39 amino acid peptide found in the salivary secretion of the Gila monster, which shares important biological actions of GLP-1, but has a longer duration of action. We examined the glucose lowering effect of subcutaneous (sc) E. Fifteen Type 2 diabetic patients: 8 diet, 7 sulphonylurea treated, age (mean q- SD) 60.3 4- 6.5 years, Body Mass Index 29.4 4- 3.1 kg m -2, HbAlc 8.5 4- 2.1%, fasting blood glucose 8.4 4- 1.7 mmol 1a , each studied on 3 occasions in a placebo-controlled double blind 24 hour study with a standard 4-meal profile. Subjects received sc E (BD, 4 /zg.m-2 18:30, 07:00), (QDS, 2/~g.m -2 18:30, 22:00, 07:00, and 12:00), or no treatment in a randomised sequence with one month washout period between tests. No significant adverse events were seen. Basal glucose 03:00 - 07:00 was reduced from (8.4 4- 1.7) mmol 1-t to (8.2 q- 2.6) mmol
1-j by BD E (p=0.77) and to (6.7 4- 1.2) mmol 1-1 by QDS E (p=0.012). Postprandial glucose increment (PPGI) after supper 18:30-22:00 was reduced from (1.64-2.0) mmol.1 "1 to (-2.74-2.9) mmol.1-1 by BD E and to (-1.84-2.7) mmol.1 -j by QDS E (p<0.0001 in each case). PPGI after breakfast 07:00-12:00was reduced from (3.44-1.6) mmol.1 -t to (-0.44-2.0) mmol.l -j by BD E and to (1.04-1.3) mmol.1 "1 by QDS E (p<0.0001 in each case). PPGI after lunch and tea 12:00 - 17:45 was reduced from (2.44-1.0) mmol.1 -I to (2.14-1.6) mmol.1 "l by BD E (p=0.38) and to (1.44-1.2) mmol.1 "1 by QDS E (p=0.012). 24 h mean glucose 18:00 17:45 was reduced from (10.5 4- 2.5) mmol 1-I to (8.6 4- 2.8) mmol 1"j by BD Exendin-4 and to (7.9 4- 1.7) mmol 1-I by QDS Exendin-4 (p<0.0001 in each case). Conclusion: Exendin-4 improved 24 h glucose exposure by lowering basal and postprandial glucose in type 2 diabetic subjects.
P237 Humalog ® Mix50 TM Versus Humalog ® Mix25 TM Before Carbohydrate-Rich Meals in Patients with Type 2 Diabetes PARIS ROACH i, Vinod Mattoo 2, Vipin Arora ~. / Eli Lilly and Company, Indianapolis, IN, United States of America; 2 The India Mix25/MixSO Study Group, Eli Lilly and Company, New Delhi, India Background and Aims: Patients with type 2 diabetes may require relatively high doses of rapid-acting insulin to control postprandial blood glucose (BG) excursions after carbohydrate (CHO)-rich meals. The objective of this study was to compare a manufactured mixture containing 50% insulin lispro (LP) and 50% NPL (Humalog ® Mix50~; Humalog ® Mix50/50 TM in the US) to a mixture containing 25% LP and 75% NPL (Humalog ® Mix25'M; Humalog ® Mix75/25 TM in the US) before a CHO-rich breakfast (approximately 70% CHO based on a typical diet in India) in patients with type 2 diabetes. Material and Methods: The study was a 16-week multicenter open-label trial in which 107 patients (64 females and 43 males) received Humalog Mix50 before breakfast plus Humalog Mix25 before the evening meal for 8 weeks and Humalog Mix25 twice daily before the same meals for 8 weeks in a randomized crossover fashion. Results: At endpoint, insulin doses were very similar for both of the regimens (AM dose 31-33 units, PM dose 26-28 units). At 6 and 8 weeks of treatment on each regimen, a standard test meal breakfast was administered, and fasting and 2-hour post-breakfast BG levels were measured. Mean fasting BG levels were not different between the treatments (Mix50, 171 4- 46 versus Mix25, 161 4- 52 mg/dL, NS). Mean 2-hour postprandial BG excursion was significantly lower during treatment with Humalog Mix50 (26 4- 56 versus 63 4- 52, p<0.001). Mean HbAjc levels were not different between the regimens (8.14% 4- 1.14% versus 8.14% 4- 1.07%, NS), nor was the percentage of patients reporting hypoglycemia (34% versus 23%, NS). Compared to pre-study treatment with human insulins, patients preferred Humalog Mix25 and Mix50, and indicated they had greater flexibility with regard to the timing of meals. Conclusions: Humalog Mix50 should be considered as a useful treatment alternative in patients with type 2 diabetes, especially in relation to high-CHO meals.
P238 Use of Insulin Lispro in Type 2 Diabetes - A 6 Month Expierence ELZBIETA BANDURSKA-STANKIEWICZ, Wioletta Zasadowska. General District Hospital Olsztyn Diabetes and Metabolic Diseases Center, Olsztyn, Poland; General District Hospital, Olsztyn Diabetes and Metabolic Diseases Center, Olsztyn, Poland Objective: 20 patients with type 2 diabetes (10 females and 10 males) aged 68 4- 4 yrs, diabetes duration 11 + yrs, were transfered from human insulin mixtures (M3,M4) administered twice daily, to lispro insulin injected immediately before eating and basal insulin (INH) administered 2 times a day.
G+P
G+I
G+2
G+5
G+I0
Numberof subjects(Intent-to-Treat) Baseline(B) FSG (retool/L) FSG A vs. P at 12 weeks % of subjects>- 1.67 mmol/LFSG A vs. B BaselineHbAlc(%) HbAlc A vs. P at 12 weeks % of subjects>_-0.7% HbAlc A vs. B
56 13.7 31% 9.7 22%
53 14.1 -2.0+ 54%# 9.8 -0.7+ 50%*
48 13.7 -1.7" 53%# 9.6 -0.5# 38%
54 13.9 -4.7+ 87%+ 10.0 -1.9+ 87%+
52 14.5 -5.4+ 90%+ 9.7 -2.1+ 92%+
Significancelevelsvs. P: # = p < 0.05 * = p < 0.005 + = p < 0.001
Conclusions: Overall, GI262570 in combination with sulfonylurea significantly improves metabolic control in the treatment of T2DM.
P232 The GLP-1 Analogue, LY307161, Potently Lowers Post Prandial Blood Glucose in Subjects with Type 2 Diabetes STEVEN J. PASCOE, Christopher Payne, Michael Trautmann. Clinical Pharmacology, Eli Lilly & Company, Erl Wood Manor, Windlesham, United Kingdom Glucagon-like peptide 1 (GLP-1) is a potent antidiabetic agent acting through stimulation of insulin release, suppressing glucagon levels, and inhibiting gastric emptying. Despite the effectiveness in patients with type 2 diabetes GLP-1 itself is unsuitable for therapeutic use due to its short biological half life. We have developed a degradation-resistant analogue LY307161with longer duration of action. The aim of this study was to examine the effects of single doses of LY307161 on glucose, insulin and glucagon in subjects with type 2 diabetes following a standardised high carbohydrate meal. 20 patients (14 males, age 60.3+1.5 yrs., BM128.3+0.8 kg/m2, duration of diabetes 1.5-18 yrs.) participated after a 7 day washout period from their previous antidiabetic medications. Each subject was dosed with placebo and 3 doses of LY307161 from the following doses, 30/~g, 100/zg, 180/zg, 300/zg, 450#g. Each dose was administered to twelve subjects. LY307161 was administered subcutaneously just prior to the consumption of a standardised meal. Blood was taken at 0, 30, 60, 120, 240 and 300 minutes post dose for glucose, insulin and glucagon assays. The high postprandial rise in blood sugar seen with placebo was attenuated in a dose dependent manner by all doses of LY307161. The maximum difference from placebo was seen at 2 hours post dosing, lasting for up to 4 hours. Compared to placebo glucose was 9.58 mmol/l lower after the 450/zg dose. Insulin levels showed an initial elevation for less than 1 hour, proportional to dose. Glucagon was suppressed for 2-4 hours showing a temporal correlation with glucose suppression. There was no evidence of any later rebound increase in glucose levels. Despite the potent lowering of glucose no hypoglycemic episodes occurred. In conclusion, LY307161
$41
demonstrated a potent effect on post prandial glucose levels in subjects with type 2 diabetes. The lowering of glucose levels was of both sufficient magnitude and duration to suggest that LY307161 could be a useful therapeutic agent in the treatment of type 2 diabetes. Furthermore the time course of the insulin and glucagon responses suggest that the role of glucagon in mediating the effects of GLP- 1 may have been underestimated.
P233 LY307161, a Giucagon Like Peptide (GLP-1) Analogue with Prolonged Action, Does Not Cause Hypoglycaemia STEVEN J. PASCOE, Christopher Payne, Eiry Roberts, Michael Trautmann. Clinical Pharmacology, Eli Lilly & Company, Erl
Wood Manor, Windlesham, United Kingdom GLP-1 is an effective and strictly glucose dependent insulin secretagogue. Since clinical use of GLP-1 is limited by the extremely short half life we have developed a longer acting analogue, LY307161. In this study we examined the effect of single doses of LY307161 on blood glucose in fasted healthy subjects over a wide range of doses. Twenty four healthy subjects were given placebo, and 3 doses of LY307161 from the following dosing levels, 5#g, 10/zg, 20/zg, 40/zg, 80p.g, 160/~g, 320/zg, 400#g, 500#g, 700/zg, 900/zg. Six subjects received each dose. LY307161 was administered by subcutaneous injection, after an overnight fast. Blood samples were taken at 0, 30, 60, 120, 240 minutes after injection for blood glucose determination. During this period no food intake was permitted. Subjects showed a dose dependent fall in blood glucose compared to placebo, which was maximal at 30 minutes and had returned to baseline at 120 minutes. The maximal fall, from baseline, for any dosing group was 33 mg/dL. The fall plateaued at a dose of 500#g. No further increase was seen with higher doses. The mean maximal fall seen at any dose was to an absolute level of 47 mg/dL and no subject experienced any symptoms of hypoglycaemia. In conclusion, LY307161 exhibited a duration of action greater than that previously demonstrated with natural GLP-1. The response proved glucose dependent and even high doses were unable to induce hypoglycaemia, in keeping with the known effects of GLP- 1.
P234 No Reactive Hypoglycemia in Type 2 Diabetic Patients after Subcutaneous Administration of GLP-1 and I.V. Glucose TINA VILSBOLL, Thure Krarup, Sten Madsbad, Jens J. Holst. Dept. of Internal Medicne E Gentofte Hospital; Dept. of Medical Physiology, The Panum Institute; Dept. of Endocrinology, Hvidovre Hospital, Copenhagen, Denmark It has previously been shown that intravenous and subcutaneous administration of glucagon-like peptide 1 (GLP-I) concomitant with i.v. glucose results in reactive hypoglycemia in healthy subjects. Since GLP-1 is also effective in type 2 diabetic patients and is presently being evaluated as a therapeutic agent in this disease, it is important to investigate whether GLP-I can cause hypoglycemia in such patients. Eight type 2 diabetic patients (age: 54(49-67) years; BMI: 31(27-38) kg/m2; HbAlc: 9.4(7.0-12.5)% and 7 matched healthy subjects (HbAic: 5.5(5.2-5.8)%, FPG: 5.4(5.0-5.7) mmol/1) were given a subcutaneous injection of 1.5 nmol GLP-1/kg body weight (maximally tolerated dose), and 15 minutes later, plasma glucose (PG) was raised to 15 mmol/l with an i.v. glucose bolus. Hypoglycemia with a PG at or below 2.5 mmol/l was seen in 5 of the 7 healthy subjects after 60-70 min, but PG spontaneously increased again, reaching 3.7 (3.3-4.0) mmol/l at 90 min. In the type 2 diabetic patients, PG fell slowly and stabilized at 8.6 (4.2-12.1) mmol/l after 80 min. In both groups, glucagon levels initially decreased, but later increased, exceeding basal levels in healthy subjects, in spite of persistent, high concentrations of GLP-1 (p<0.02).
$42
Poster Session 1
Conclusion: Subcutaneous GLP-1 plus i.v. glucose induced reactive hypoglycemia in healthy subjects, but not in type 2 diabetic patients. Therefore, a GLP-1 based therapy would not be expected to be associated with an increased risk of hypoglycemia in type 2 diabetes mellitus.
P235 Antidiabetic Effect of Neoflavonoid Coutareagenin in STZ Diabetic Rats and Diabetic Menopausal Women R. KOREC j, M. Korecovfi 2, K.H. Sensch 3, T. Zoukas 3. J Diabetes Res Lab.Med.Fac.Univ., Ko~ice; 2 IDF President W.Mayes Jr.Diabet.Dept., Tren6fn, Slovakia (Slovak Republic); 3 Gehrlicher Labor, Eurasburg, Germany Extracts from the bark of southamerican Hintonia/Couterea/latiflora are used by indigenous people as antidiabetic agent and in Germany its alcoholic extract Sucontral-R for decades by people with mild diabetes. The first author has proven that Sucontral R depressed in dosis 100 or 200mg/kg after gavage/IG/in wakeful STZ-diabetic rats of both gender hyperglycemia of 21 up to 29 mmol/l by 32 up to 42% after 2 and 4h, and this dosis administered in drinking water depressed hyperglycemia from 19 to 13mmol after one-two days. Zoukas synthetized the active substance of Sucontral, CoutareagenirdCTR/, a neoflavonoid, which dissolved in Propylen/PRG/or Polyethylen-glycol/PEG/, administered IG in dose 3, 6, 9 and 18mg/kg to 208 STZ chronically diabetic rats, with initial glycemia ranging between 20 and 39mmol/l, depressed it by 21 up to 29%, even after 14h of fasting. CTR dissolved in PRG or PEG, in dose lmg/kg IV, depressed in further 94 rats hyperglycemia of 24 up to 26mmol/l by 25 up to 35%, in which tolbutamide/60mg&g IV/, highly effective in non-diabetic rats, caused a decrease by 7% only. Because after repeated oral, IG, IV administration of Sucontral or CTR in rats no toxic symptoms were observed, eight instructed, complying postmenopausal diabetic women, not well compensated by diet or sulphonylureas, with mean age 56.6 and 9.3y of diabetes duration, took daily before three meals 2ml of Sucontral for 3 up to 12 months. After three months already, their initial fasting glycemia fell from 114-1.9/+SD/to 8.4q-lmmol, and their postprandial glycemia from 154-1.8 to 1 lq-l/p < 0.057 and HbAlc from 94-0.96 to 8.34-1.2, without changes in hepatic ALT, GMT and ALP. Moreover, patients reported feelings of well-being, disappearance of disagreable vegetative symptoms as sweating in the upper part of their body, of fatigue, anorhexia and dyspepsia. Conclusion: After proving the hyperglycemia depressing effectivity of Sucontral and of its active principle neoflavonoid Coutareagenin in 336 STZ. diabetic, tolbutemide resistant rats, without any signs of toxicity, authors document its antidiabefic activity also in postmenopausal diabetic women with additional beneficial effects on their vegetative symptoms.
P236 Subcutaneous Exendin-4 Improves 24 Hour Glucose Exposure in Type 2 Diabetes H. MAKSOUD, B.A. Barrow, S.E. Manley, J.C. Levy. Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, United Kingdom Exendin-4 (E) is a 39 amino acid peptide found in the salivary secretion of the Gila monster, which shares important biological actions of GLP-1, but has a longer duration of action. We examined the glucose lowering effect of subcutaneous (sc) E. Fifteen Type 2 diabetic patients: 8 diet, 7 sulphonylurea treated, age (mean q- SD) 60.3 4- 6.5 years, Body Mass Index 29.4 4- 3.1 kg m -2, HbAlc 8.5 4- 2.1%, fasting blood glucose 8.4 4- 1.7 mmol 1a , each studied on 3 occasions in a placebo-controlled double blind 24 hour study with a standard 4-meal profile. Subjects received sc E (BD, 4 /zg.m-2 18:30, 07:00), (QDS, 2/~g.m -2 18:30, 22:00, 07:00, and 12:00), or no treatment in a randomised sequence with one month washout period between tests. No significant adverse events were seen. Basal glucose 03:00 - 07:00 was reduced from (8.4 4- 1.7) mmol 1-t to (8.2 q- 2.6) mmol
1-j by BD E (p=0.77) and to (6.7 4- 1.2) mmol 1-1 by QDS E (p=0.012). Postprandial glucose increment (PPGI) after supper 18:30-22:00 was reduced from (1.64-2.0) mmol.1 "1 to (-2.74-2.9) mmol.1-1 by BD E and to (-1.84-2.7) mmol.1 -j by QDS E (p<0.0001 in each case). PPGI after breakfast 07:00-12:00was reduced from (3.44-1.6) mmol.1 -t to (-0.44-2.0) mmol.l -j by BD E and to (1.04-1.3) mmol.1 "1 by QDS E (p<0.0001 in each case). PPGI after lunch and tea 12:00 - 17:45 was reduced from (2.44-1.0) mmol.1 -I to (2.14-1.6) mmol.1 "l by BD E (p=0.38) and to (1.44-1.2) mmol.1 "1 by QDS E (p=0.012). 24 h mean glucose 18:00 17:45 was reduced from (10.5 4- 2.5) mmol 1-I to (8.6 4- 2.8) mmol 1"j by BD Exendin-4 and to (7.9 4- 1.7) mmol 1-I by QDS Exendin-4 (p<0.0001 in each case). Conclusion: Exendin-4 improved 24 h glucose exposure by lowering basal and postprandial glucose in type 2 diabetic subjects.
P237 Humalog ® Mix50 TM Versus Humalog ® Mix25 TM Before Carbohydrate-Rich Meals in Patients with Type 2 Diabetes PARIS ROACH i, Vinod Mattoo 2, Vipin Arora ~. / Eli Lilly and Company, Indianapolis, IN, United States of America; 2 The India Mix25/MixSO Study Group, Eli Lilly and Company, New Delhi, India Background and Aims: Patients with type 2 diabetes may require relatively high doses of rapid-acting insulin to control postprandial blood glucose (BG) excursions after carbohydrate (CHO)-rich meals. The objective of this study was to compare a manufactured mixture containing 50% insulin lispro (LP) and 50% NPL (Humalog ® Mix50~; Humalog ® Mix50/50 TM in the US) to a mixture containing 25% LP and 75% NPL (Humalog ® Mix25'M; Humalog ® Mix75/25 TM in the US) before a CHO-rich breakfast (approximately 70% CHO based on a typical diet in India) in patients with type 2 diabetes. Material and Methods: The study was a 16-week multicenter open-label trial in which 107 patients (64 females and 43 males) received Humalog Mix50 before breakfast plus Humalog Mix25 before the evening meal for 8 weeks and Humalog Mix25 twice daily before the same meals for 8 weeks in a randomized crossover fashion. Results: At endpoint, insulin doses were very similar for both of the regimens (AM dose 31-33 units, PM dose 26-28 units). At 6 and 8 weeks of treatment on each regimen, a standard test meal breakfast was administered, and fasting and 2-hour post-breakfast BG levels were measured. Mean fasting BG levels were not different between the treatments (Mix50, 171 4- 46 versus Mix25, 161 4- 52 mg/dL, NS). Mean 2-hour postprandial BG excursion was significantly lower during treatment with Humalog Mix50 (26 4- 56 versus 63 4- 52, p<0.001). Mean HbAjc levels were not different between the regimens (8.14% 4- 1.14% versus 8.14% 4- 1.07%, NS), nor was the percentage of patients reporting hypoglycemia (34% versus 23%, NS). Compared to pre-study treatment with human insulins, patients preferred Humalog Mix25 and Mix50, and indicated they had greater flexibility with regard to the timing of meals. Conclusions: Humalog Mix50 should be considered as a useful treatment alternative in patients with type 2 diabetes, especially in relation to high-CHO meals.
P238 Use of Insulin Lispro in Type 2 Diabetes - A 6 Month Expierence ELZBIETA BANDURSKA-STANKIEWICZ, Wioletta Zasadowska. General District Hospital Olsztyn Diabetes and Metabolic Diseases Center, Olsztyn, Poland; General District Hospital, Olsztyn Diabetes and Metabolic Diseases Center, Olsztyn, Poland Objective: 20 patients with type 2 diabetes (10 females and 10 males) aged 68 4- 4 yrs, diabetes duration 11 + yrs, were transfered from human insulin mixtures (M3,M4) administered twice daily, to lispro insulin injected immediately before eating and basal insulin (INH) administered 2 times a day.