or glipizide in NIDDM patients with secondary failure on oral hypoglycaemic agents

The Netherlands

J O U R N A L OF MEDICINE ELSEVIER

Netherlands Journal of Medicine 47 (1995) A59-A64

Dutch Association for Diabetes Research (NVDO) and Flemish Research Group for Diabetology (VWWD) Abstracts of papers presented at the meeting held in Amsterdam on 20 May, 1995 Major life events and prevalence of previously unknown diabetes in the Hoorn Study. H. de Vries, J.M. Mooy, P.A. Grootenhuis, L.M. Bouter, R.J. Heine. Instituut roar Extra-

muraal Geneeskundig Onderzoek, Vrije Universiteit te Amsterdam, Vakgroep Huisarts-, Verpleeghuis- en Sociale Geneeskunde, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands. Objective: To explore the effect of major stressful life events on the prevalence of diabetes and on parameters of glucose metabolism. Methods: In a general Caucasian population sample in the age category of 50-74 years and previously unknown with diabetes (n = 2262), the number of major stressful life events over the past 5 years was assessed by self-report, preceding an Oral Glucose Tolerance Test (OGTT). The diagnosis of diabetes was based on the WHO 1985 criteria. Body Mass Index (BMI), Waist Hip Ratio (WHR), fasting and 2-h post load (75 g) plasma glucose were measured in the full sample, and fasting and 2-h ~specific insulin and proinsulin were determined in a random sample ( n = 563). Sex and age were adjusted for in: the analysis. Results: In 112 cases diabetes was newly diagnosed. Of all participants 18% reported /> 3 stressful life events. In the latter group diabetes sex- and age-adjusted prevalence was 8.0%, compared with 4.7% in subjects with < 3 events reported (p = 0.028). In the subgroup with a positive family history of diabetes (n = 593) these prevalences were 12.2% and 5.4%, respectively (p = 0.009). Among newly detected diabetes patients those reporting >~3 events had a median fasting insulin level of 122 pmol/l and a median 2-h post-load insulin level of 708 pmol/l, compared with 98 and 459 pmol/l, respectively, in those with < 3 events (fasting insulin: p = 0.090; 2-h post-load insulin: p = 0.018). The associations with insulin were independent of WHR, but partly explained by BMI. The ratio fasting proinsulin/insulin was not associated with the numbe~ of stressful life events in newly detected diabetes. Conclusion: Our findings are consistent with the hypothesis that stressful life events contribute to the onset of diabetes,

especially in the genetically predisposed. A possible mechanism is an aggravating influence of stressful events on insulin resistance.

Efficacy of bedtime NPH insulin alone, as compared to combination with metformin and/or glipizide in NIDDM patients with secondary failure on oral hypoglycaemic agents. R.J. Heine 1, A. Scheen 2, L. Van Gaal 3 H. Schmitt 4 P.S. van der Wal 1 and the Benelux SWIM study group, l Amsterdam,

Netherlands; 2Liege, 3Antwerp, 4Brussels, Belgium. In this international multicentre study we assessed the effect of 4 different therapies on glycaemic control in NIDDM patients with secondary failure on oral hypoglycaemic agents. We included 133 patients, aged 40-75 years [mean 59.3 (SD 8.2) yr.], body mass index 29.0 (3.0) kg/m 2, fasting plasma glucose levels higher than 7.9 mmol/l during treatment with glipizide (15 mg) and,metformin (1700 mg) for at least 2 months prior to randomisation. Patients were randomly allocated to treatment with bedtime NPH-insulin alone (A), i n combination with metformin (B) or with glipizide (C) or with glipizide and metformin (D) for 6 months. Fasting plasma glucose, HbAlc, BMI and home blood glucose profiles (HBGP) were assessed at baseline and after 6, 12 and 26 weeks following insulin treatment. At inclusion, fasting glucose, BMI and HBGP were comparable in all groups. At 26 weeks, fasting plasma glucose levels had decreased from 13.4 to 10.8 (A), from 13.6 to 9.8 (B), from 13.4 to 10.5 (C) and from 13.5 to 9.5 (D) mmol/l (all p < 0.001) whereas only in group D was a significant decline of the Z-scores of HbAI~ observed (A Z-score of HbAlc: 1.7 p < 0.02). Daily insulin dosages at 26 weeks were 42 (17), 34 (23), 29 (18) and 20 (19) units in Groups A, B, C and D, respectively. Mean daytime glycaemia decreased significantly in Group D only, from 11.3 (3.0) to 8.5 (2.7) mmol/l (p < 0.001). No differences between groups were observed for changes in BMI. Conclusion: We conclude that in NIDDM patients with secondary failure on oral hypoglycaemic agents, the combination of bedtime NPH insulin with glipizide and metformin

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Abstracts/Netherlands Journal of Medicine 47 (1995) A59-A64

provides the most effective therapy in terms of HbA1 c and mean daytime glycaemia.

Energy expenditure during pre-prandial administration of Lispro insulin analogue in IDDM patients. M.A.J.M. Jacobs, E. Keulen, K. Kanc, S. Casteleijn, R.J. Heine. Department of Endocrinology, Free University Hospital, De Boelelaan 1117, 1081 H V Amsterdam, Netherlands. The objective of this study was to evaluate the effect of a rapidly absorbed short acting insulin analogue (Lispro or LP) on energy expenditure. Twelve well-controlled type I diabetics (HbAlc 6.8+_0.9%; 8 males) were treated for 1 month with either LP at mealtimes or human insulin (HI) 30 min prior to the meals and NPH insulin at bedtime, in a randomized, open labeled, cross-over study. At the end of both study periods the resting energy expenditure (REE) and the diet-induced thermogenesis (DIT) of a mixed meal were determined using indirect calorimetry. Blood samples were taken for assessments of glucose, insulin, glucagon and metabolites (lactate, free fatty acids, glycerol and /3-hydroxybutyrate). On the morning of the tests HbAlc and body weight were very similar; LP vs. HI, 6.7+0.8 vs. 6.5+0.7%, p = 0.4 and 78.1 + 8.1 vs. 78.7_+7.5 kg, n.s., respectively. The blood glucose excursion after the meal was lower for LP, although not significantly. Insulin profiles following LP as compared to HI injection rose faster, peaked earlier (61 + 12 vs. 111 _+48 min, p < 0.01) and the total area under the curve of insulin was greater (836_+429 vs, 634_+367 p m o l , l - l . h , p <0.01). REE was lower during LP treatment (1818_+ 287 vs. 1949 _+289 kcal, p < 0.05). The DIT measured for 4 h following the standard meal tended to be higher for LP treatment (53.3_+33.2 vs. 37.3 _+28.3 kcal, p = 0.06) but was significantly higher during the first 2 h (26_+ 14.3 vs. 17_+ 11.1 kcal, p < 0.05). Substrate oxidation was similar for both treatments. Conclusion: Insulin Lispro showed a more physiological insulin profile with a tendency to lower postprandial glucose excursions. Moreover, the insulin kinetics of insulin Lispro results in a lower resting energy expenditure and a higher meal-induced initial thermogenic effect. Predicting NIDDM: enhancing efficiency in screening. J.B. Ruige 2, j N.D. de Neeling 1 L.M. Bouter 1.2 R.J. Heine 1.3. /, " ' , nstttute for Research in Extramural Medicine, Departments of 2 Epidemiology and Biostatistics and 3 Internal Medicine, Vrije Universiteit, Van der Boechorststraat 7, 1081 BT Amsterdam, Netherlands. We investigated to what extent non-insulin-dependent diabetes mellitus (NIDDM) could be predicted on the basis of data from history, anthropometry and a fasting blood sample, and whether this prediction could be used to enhance the efficiency of screening for NIDDM. A general population sample of 2391 50-74-year-old Caucasian subjects, not treated with insulin or oral hypoglycaemic agents, underwent an oral glucose tolerance test (OGTT). Fifty-six subjects with a fasting plasma glucose /> 7.8 mmol/1 were excluded from the analysis. Of the remaining 2335 subjects, 73 had diabetes on the basis of a 2-h post-load plasma glucose value >/11.1 mmol/l.

A backward stepwise multiple logistic regression analysis was carried out with diabetes as the dependent variable. Age, sex, positive family history, waist to hip ratio, fasting glucose, triglycerides, and LDL-cholesterol proved to be independently and significantly (p < 0.05) associated with the presence of diabetes. Hypertension, body mass index, HDL and total cholesterol were not includgd in the final regression model. For each study subject the risk of diabetes predicted by the regression equation was computed, and, using 3 different cut-off values, the subjects at risk of diabetes were identified. Assuming that only in those subjects an OGTT would be performed, we found that the performance of an OGTT in 41, 27 or 20% of the total population would result in the identification of 92, 88 or 85% of all subjects with diabetes, respectively. In addition, among the non-diabetic subjects who would undergo an OGTI', 20, 26 or 28% would have an impaired glucose tolerance (IGT), representing 77, 65 and 56% of all subjects with IGT in this population, respectively. Conclusion: The number of OGTTs to be performed can be reduced, and, thereby, the efficiency of a NIDDM screening program enhanced considerably, by adequately taking into account data which can be obtained from history, anthropometry and a fasting venous blood sample.

The influence of night-time continuous subcutaneous insulin infusion (CSII) therapy on counterregulatory hormonal responses and warning symptoms of hypoglycaemia in IDDM patients during clamping. K. Kanc, E. Keulen, M.A.J.M. Jacobs, C. Popp-Snijders 1, K. Nasseri, R.J. Heine. Department of Endocrinology, 1 Department of Neurology, Free University Hospital, De Boelelaan 1117, 1081 H V Amsterdam, Netherlands. Good glycaemic control is associated with a higher risk of hypoglycaemias. Moreover, the absorption of the bed-time intermediate-acting insulin (NPH), administered as a part of the multiple injection regimen, is highly variable and leads to frequent nocturnal hypoglycaemias. In an open, randomized, cross-over study, with 2-month study periods, the effect of replacing the bed-time NPH insulin injection by night-time CSII was studied on the counterregulatory hormonal (CR) response as well as on the autonomic and neuroglycopenic wanting symptoms of hypoglycaemia during a standardized, stepwise, hyperinsulinaemic, hypoglycaemic clamp, performed in steps of 0.5 mmol/l from 4.0 mmol/1 to a glucose nadir of 2.5 mmol/l. So far, 6 persons with IDDM (all male), mean age 29.2 (SD 5.49) years, duration of diabetes 12.2 (2.9) years, body mass index 22.3 (1.7) kg-m -2, HbAlc 7.6(0.7)% (norm. < 6.1%) with no autonomic neuropathy, completed the study. After the 2 week run-in period, patients were randomly allocated to either therapy group. HbAlc values at the end of the CSII and NPH injection therapy periods were similar: 7.5 (1.1) vs. 7.2 (1.0)%, n.s. CSII therapy as compared with NPH injection therapy resulted in an increased CR response incremental area under the curve (AUC): for epinephrine 1.8 (SD 1.6) vs. 0.6 (1.3) nmol/1.h (p < 0.05), for growth hormone 57.7 (49.6) vs. 36.7 (48.7) ~ g / l . h (n.s.) and for PP 134.4 (227.3) vs. 65.8 (86.8) p m o l / l , h (n.s.). The threshold for