5. METHODS
7.4. Choice of the insulin treatment regimen…
In type 2 diabetes there are abnormalities in insulin secretion and insulin action, so it is reasonable to treat them both. If the hypothesis of progressively deteriorating β-cell function in type 2 diabets (286) is correct, insulin therapy will ultimately be re-quired by all of type 2 diabetic patients if the patient lives long enough.
We have shown that similar metabolic control can be achieved with different simple combination treatment regimens as with multiple insulin injections (FINMIS and FINFAT). In addition the FINFAT study showed that treatment with bedtime insulin and metformin gives best glycemic control and is associated with less hypoglycemia and weight gain than other bedtime insulin regimens.
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Many factors influence the choice of insulin treatment regimen, such as the patients’
psychosocial background, lifestyle, propensity for hypoglycemia, age, obesity and ability of the patient to self-administer insulin. Thus, there is no universally applica-ble regimen. It is therefore important to carefully examine these factors in each indi-vidual patient before recommending an insulin treatment regimen, also including the patients motivation.
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SUMMARY AND CONCLUSIONS
I In poorly controlled type 2 diabetic patients receiving oral hypoglycemic drug therapy, the addition of NPH insulin in the evening improves glycemic control in a similar manner as a two-insulin-injection therapy regimen and multiple-insulin-therapy regimen, but induces less weight gain and hyperinsulinemia.
II Combination therapy with bedtime insulin plus metformin prevents weight gain and seems superior to other bedtime insulin regimens with respect to improvement in glycemic control and frequency of hypoglycemia.
III S.c. insulin absorption is a determinant of the action of s.c. insulin but not of the insulin dose. Actions of s.c. and i.v. insulin to suppress FFA are significantly correlated. The actions of i.v. insulin and s.c. insulin are both correlated with the in-sulin dose. Of various measurements of adiposity, the % hepatic fat is the parameter best correlated with hepatic sensitivity to insulin and insulin dose.
These data demonstrate that the major reason for inter-individual variation in insu-lin requirements in type 2 diabetes is the variation in insuinsu-lin action. Variation in hepatic fat content may influence insulin requirements via an effect on the sensitiv-ity of EGO to insulin.
IV Improvement in glycemic control by administration of insulin alone or insulin combined with either glibenclamide, metformin, or both agents induces a sustained decrease in sE-selectin, the magnitude of which seems to be dependent on the de-gree of improvement in glycemia. sE-selectin might provide a marker of effects of treatment of chronic hyperglycemia on endothelial activation.
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ACKNOWLEDGEMENTS
This work was carried out first as multi-center studies conducted from the Department of Medicine at the Helsinki University Central Hospital and then at the Department of Medicine, Division of Diabetes at the Helsinki University Central Hospital. First of all, I am deeply grateful to Professor Kalevi Pyörälä for inspiring me to dedicate myself to internal medicine and encouraging me - right from the beginning of my career- to do research, and also for all the support he has offered to me and my family through the years. Also, I can not express the appreciation I have for Professor Marja-Riitta Taskinen, who has been a dear friend since the 60s and has helped and supported me throughout the making of this thesis.
I want to express my gratitude to my supervisor Professor Hannele Yki-Järvinen for her ex-pert and tireless guidance on this work. Without her inspiration, ideas and her incomparable, indeed singular, knowledge and assistance this work would have been an utter impossibility.
Very warm thanks to Professor Ulf Smith from the Lundberg Laboratory for Diabetes Re-search, Shalgrenska University Hospital, Department of Internal Medicine, Gothenburg and Professor Matti Uusitupa from Depratment for Clinical Nutrition, University of Kuopio, for constructive review of the manuscript.
For my enthusiasm for working with diabetes I owe a debt of gratitude to both Professor Tero Kangas and Professor Jorma Viikari, all those conversations we have shared during all these years have given me so much.
Without my young colleagues at the Division of Diabetes at the Helsinki University Central Hospital this work would have never been completed. Satu Vehkavaara ja Jukka Westerbacka taught me a plethora of technical aspects of research and without concern for their troubles sent me those research material which I could not obtain from Kotka. They also became my dear friends, a development for which I am more than grateful. And I hold Robert Bergholm and Juha Vakkilainen to also be members of this group on charming young colleagues with whom I had the pleasure of working with.
Anna-Maija Häkkinen, MD, from department of Oncology University of Helsinki, thank you for superbly performing spectroscopies and magnetic scans for my research, and for many interesting and informative conversations. Juha Halavaara is responsible for the fact that I had the examination facilities available as I needed in the department of radiology, a large thank you is not even nearly sufficient.
I also want to express my heartfelt gratitude to Sari Haapanen, Kati Tuomola, Katja Tuomi-nen, Hannele Hilden, Kikka Runeberg, Takashi Goto and Pentti Pölönen for excellent techni-cal assistance and Maaria Puupponen, Sirpa Marttinen-Arponen and Gunilla Lindell for their skillful secretarial and other kind of help, also a big thank you for Soile Aarnio for her always speedy assistance on producing the figures for my thesis, even when then changes came in thick and fast. Arja Nikkinen ja Kaiju Sysikumpu, thank you for sending all those reference materials.
Every colleague and nurse who took part in the multi-center FINMIS and FINFAT studies deserves a mention and my gratitude: doctors Marjut Kauppila, Eila Kujansuu, Jorma Lahti, Tapani Marjanen, Katriina Nikkilä, Leo Niskanen, Sulo Rajala, Seppo Salo, Pentti Seppälä,
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Timo Tulokas, Raimo Vanamo (deceased), Jorma Viikari, Jukka Karjalainen and nurses Marjatta Heikkilä, Lisa Flink, Raija Härkönen, Liisa Hyvärinen, Jaana Jäkälä, Margit Kalk-kila, Anneli Karjalainen (deceased), Marja-Leena Kekäläinen, Riitta Nopola, Leena Pekkonen and especially Mare Riihelä, with whom I have the privilege to work with every day.
We had many a good time, all of us who were doing the multi-center research, all those memorable and often hilarious meetings we had in Kotka and elsewhere. The hiking in Lap-land, arranged by Marjatta Heikkilä, Timo Tulokas and Liisa Hyvärinen, was only the best of the bunch. I also want to take this opportunity to remeber all the happy moments our now unfortunately deceased colleague Raimo Vanamo provided for our group. His hunting and fishing legends were - oddly enough, now that I think of it - always captivating.
Kati Nikkilä, you are a very close, personal friend and always ready to help a colleague.
Thank you.
My dear friend and colleague Terttu Toivonen deserves a very special thank you for putting me up in her apartment as I was conducting my research and for never uttering a complaint for all that time. And all the conversations and saunas ( that is saunaillat for those familiar with the jargon), they gave me a wider perspective on life.
These studies could not have been performed without the subjects and patients who volun-teered to participate. My greatest gratitude for their help.
All my colleagues at Internal Medicine at the Kymenlaakso Central Hospital were incredibly understanding every time I needed a leave of absence.
For proofreading my manuscript and upholding my interest in culture while doing this re-search I thank my good neighbor and colleague Alexander van Assendelft, and also his wife Margaret for all those good times at concerts and the opera.
I also owe a very big thank you for Juhani Dufva and Juha Rissanen for their patience and success in teaching me statistical mathematics. And, while considering the pedagogical issues, Robert Carey can not be omitted, without his tutoring my English would not have been up to the task.
And last, but definitely not least, I thank my beloved husband Osmo and my two sons Ransu and Rieti, for their patience, support and assistance at the times when I had almost given up hope. If my sons had not been there every time the computers refused to co-operate, I surely would have despaired. I also wish to express my deepest respect for my father, 90 years old as of writing this, who - even when I was still a child- taught me to respect education and sci-ence and have empathy for our fellow man. And finally thank my sister Liisa, who has always assisted me when I have asked.
This work has financially been supported by Academy of Finland and Finnish Diabetes Re-search Foundation.
Kotka November 2001
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Reference List
1. The University Group Diabetes Program. A study of the effect of hypoglycemic agents on vascular complications in patients with adult-onset diabetes II. Mor-tality results. Diabetes 1970;19:785-830
2. Report of the National Commission on Diabetes to the Congress of United States.
1975. Bethesda, MD: US Department of Health, Education and Welfare, United States National Commission on Diabetes.
3. Classification and diagnosis of diabetes mellitus and other categories of glucose intol-erance. National Diabetes Data Group. Diabetes 1979;28:1039-1057
4. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VIII. Evaluation of insulin therapy: final report. Diabetes 1982;31 Suppl 5:1-81
5. Diabetes Mellitus: Report of a WHO Study Group. 1985. Geneva, World Health Org., World Health Organization.
6. ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography. Eur Heart J 1993;14:8-17
7. Hypertension in Diabetes Study (HDS): II. Increased risk of cardiovascular complica-tions in hypertensive type 2 diabetic patients. J Hypertens 1993;11:319-325 8. The absence of glycemic treshold for the development of long-term complications: the
perspective of The Diabetes Control and Complications Trial. Diabetes 1996;
45(10)1289-1298
9. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.N Engl J Med 1993;329:977-986
10. U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group.Diabetes 1995;44:1249-1258
11. United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of ran-domly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years.
BMJ 1995;310:83-88
12. The absence of a glycemic threshold for the development of long-term complications:
the perspective of the Diabetes Control and Complications Trial. Diabetes 1996;45:1289-1298
123
13. Effect of intensive blood-glucose control with metformin on complications in over-weight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998a;352:854-865
14. Intensive blood-glucose control with sulphonylureas or insulin compared with con-ventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998b;352:837-853
15. Tight blood pressure control and risk of macrovascular and microvascular complica-tions in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.
BMJ 1998;317:703-713
16. UKPDS 28: a randomized trial of efficacy of early addition of metformin in sulfonyl-urea-treated type 2 diabetes. U.K. Prospective Diabetes Study Group. Diabe-tes Care 1998;21:87-92
17. Supplement 1. American Diabetes Association: clinical practice recommendations 2000. Diabetes Care 2000;23 Suppl 1:S1-116
18. Type 2 diabetes in children and adolescents. American Diabetes Association. Diabe-tes Care 2000;23:381-389
19. Abbott RD, Donahue RP, Kannel WB, Wilson PW: The impact of diabetes on survival following myocardial infarction in men vs women. The Framingham Study.
JAMA 1988;260:3456-3460
20. Abo K, Mio T, Sumino K: Comparative analysis of plasma and erythrocyte 7-ketocholesterol as a marker for oxidative stress in patients with diabetes mel-litus. Clin Biochem 2000;33:541-547
21. Abraira C, Colwell JA, Nuttall FQ, Sawin CT, Nagel NJ, Comstock JP, Emanuele NV, Levin SR, Henderson W, Lee HS: Veterans Affairs Cooperative Study on gly-cemic control and complications in type II diabetes (VA CSDM). Results of the feasibility trial. Veterans Affairs Cooperative Study in Type II Diabetes.
Diabetes Care 1995;18:1113-1123
22. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR: Association of systolic blood pressure with macro-vascular and micromacro-vascular complications of type 2 diabetes (UKPDS 36):
prospective observational study. BMJ 2000;321:412-419
23. Albertini JP, Valensi P, Lormeau B, Aurousseau MH, Ferriere F, Attali JR, Gattegno L: Elevated concentrations of soluble E-selectin and vascular cell adhesion molecule-1 in NIDDM. Effect of intensive insulin treatment. Diabetes Care 1998;21:1008-1013
24. Albertini JP, Valensi P, Lormeau B, Vaysse J, Attali JR, Gattegno L: Soluble L-selectin level is a marker for coronary artery disease in type 2 diabetic patients.
Diabetes Care 1999;22:2044-2048
124
25. Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I: Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link be-tween visceral fat accumulation and vascular disease. Diabetes 1997;46:860-867
26. Almer LO: Effect of chlorpropamide and gliclazide on plasminogen activator activity in vascular walls in patients with maturity onset diabetes. Thromb Res 1984;35:19-25
27. Alzaid AA, Dinneen SF, Turk DJ, Caumo A, Cobelli C, Rizza RA: Assessment of insulin action and glucose effectiveness in diabetic and nondiabetic humans. J Clin Invest 1994;94:2341-2348
28. Amador-Licona N, Guizar-Mendoza J, Vargas E, Sanchez-Camargo G, Zamora-Mata L: The short-term effect of a switch from glibenclamide to metformin on blood pressure and microalbuminuria in patients with type 2 diabetes mellitus. Arch Med Res 2000;31:571-575
29. Amos AF, McCarty DJ, Zimmet P: The rising global burden of diabetes and its com-plications: estimates and projections to the year 2010. Diabet Med 1997;14 Suppl 5:S1-85
30. Anderson PJ, Chan JC, Chan YL, Tomlinson B, Young RP, Lee ZS, Lee KK, Me-treweli C, Cockram CS, Critchley JA: Visceral fat and cardiovascular risk factors in Chinese NIDDM patients. Diabetes Care 1997;20:1854-1858 31. Arner P: Not all fat is alike. Lancet 1998;351:1301-1302
32. Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL: Pio-glitazone hydrochloride monotherapy improves glycemic control in the treat-ment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000;23:1605-1611
33. Asplund-Carlson A, Hamsten A, Wiman B, Carlson LA: Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentra-tion, insulin levels and insulin sensitivity: studies in randomly selected normo-and hypertriglyceridaemic men. Diabetologia 1993;36:817-825
34. Atkinson MA, Maclaren NK: The pathogenesis of insulin-dependent diabetes mellitus.
N Engl J Med 1994;331:1428-1436
35. Austin MA, Breslow JL, Hennekens CH, Buring JE, Willett WC, Krauss RM: Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988;260:1917-1921
36. Aviles-Santa L, Sinding J, Raskin P: Effects of metformin in patients with poorly controlled, insulin-treated type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999;131:182-188
37. Bachmann W, Lotz N, Mehnert H, Rosak C, Schoffling K: Effectiveness of combined treatment with glibenclamide and insulin in secondary sulfonylurea failure. A
125
controlled multicenter double-blind clinical trial. Dtsch Med Wochenschr 1988;113:631-636
38. Bailey CJ: Biguanides and NIDDM. Diabetes Care 1992;15:755-772
39. Bak JF, Moller N, Schmitz O, Saaek A, Pedersen O: In vivo insulin action and muscle glycogen synthase activity in type 2 (non-insulin-dependent) diabetes mellitus:
effects of diet treatment. Diabetologia 1992;35:777-784 40. Balfour JA, Faulds D: Repaglinide. Drugs Aging 1998;13:173-180
41. Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Haring HU: Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insu-lin resistance. Circulation 2000;101:1780-1784
42. Bannan S, Mansfield MW, Grant PJ: Soluble vascular cell adhesion molecule-1 and E-selectin levels in relation to vascular risk factors and to E-E-selectin genotype in the first degree relatives of NIDDM patients and in NIDDM patients. Diabe-tologia 1998;41:460-466
43. Barrett-Connor EL, Cohn BA, Wingard DL, Edelstein SL: Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study. JAMA 1991;265:627-631
44. Bastyr EJ, Johnson ME, Trautmann ME, Anderson JH, Vignati L: Insulin lispro in the treatment of patients with type 2 diabetes mellitus after oral agent failure. Clin Ther 1999;21:1703-1714
45. Basu A, Basu R, Shah P, Vella A, Johanson CM NK, Schwenk WF RR: Type 2 dia-betes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. Diabetes 2001;50:1351-1362
46. Bauman W, Shaw S, Jayatilleke E, Spungen A, Herbert V: Icreased intake of Calcium Reverses Vitamin B 12 Malabsorption Induced by Metformin. Diabetes Care 2000;23:1227-1231
47. Baynes C, Henderson AD, Anyaoku V, Richmond W, Johnston DG, Elkeles RS: The influence of regional adiposity on atherogenic risk factors in men and women with type 2 diabetes. Diabet Med 1991;8:458-463
48. Baynes JW: Role of oxidative stress in development of complications in diabetes.
Diabetes 1991;40:405-412
49. Bearn AG, Billing BH, Scherloc S: Hepatic glucose output and hepatic insulin sensi-tivity in diabetes mellitus. Lancet 1951;698-701
50. Behar S, Boyko V, Reicher-Reiss H, Goldbourt U: Ten-year survival after acute myo-cardial infarction: comparison of patients with and without diabetes. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Am Heart J 1997;133:290-296
126
51. Belch JJ, Shaw JW, Kirk G, McLaren M, Robb R, Maple C, Morse P: The white blood cell adhesion molecule E-selectin predicts restenosis in patients with intermit-tent claudication undergoing percutaneous transluminal angioplasty. Circula-tion 1997;95:2027-2031
52. Bell PM, Firth RG, Rizza RA: Effects of hyperglycemia on glucose production and utilization in humans. Measurement with [23H]-, [33H]-, and [614C]glucose.
Diabetes 1986;35:642-648
53. Bell PM, Firth RG, Rizza RA: Assessment of the postprandial pattern of glucose me-tabolism in nondiabetic subjects and patients with non-insulin-dependent dia-betes mellitus using a simultaneous infusion of [2(3)H] and [3(3)H] glucose.
Metabolism 1989;38:38-45
54. Bergman RN, Finegood DT, Ader M: Assessment of insulin sensitivity in vivo. En-docr Rev 1985;6:45-86
55. Bergstrom RW, Newell-Morris LL, Leonetti DL, Shuman WP, Wahl PW, Fujimoto WY: Association of elevated fasting C-peptide level and increased intra-abdominal fat distribution with development of NIDDM in Japanese-American men. Diabetes 1990;39:104-111
56. Billingham MS, Milles JJ, Bailey CJ, Hall RA: Lipoprotein subfraction composition in non-insulin-dependent diabetes treated by diet, sulphonylurea, and insulin.
Metabolism 1989;38:850-857
57. Birkeland KI, Furuseth K, Melander A, Mowinckel P, Vaaler S: Long-term random-ized placebo-controlled double-blind therapeutic comparison of glipizide and glyburide. Glycemic control and insulin secretion during 15 months. Diabetes Care 1994;17:45-49
58. Blackshear PJ, Roussell AM, Cohen AM, Nathan DM: Basal-rate intravenous insulin infusion compared to conventional insulin treatment in patients with type II diabetes. A prospective crossover trial. Diabetes Care 1989;12:455-463 59. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D: Relationships between insulin
secretion, insulin action, and fasting plasma glucose concentration in nondia-betic and noninsulin-dependent dianondia-betic subjects. J Clin Invest 1984;74:1238-1246
60. Bogardus C, Taskinen MR, Zawadzki J, Lillioja S, Mott D, Howard BV: Increased resting metabolic rates in obese subjects with non-insulin-dependent diabetes mellitus and the effect of sulfonylurea therapy. Diabetes 1986;35:1-5
61. Bondy PK, James DF, Farrar BW: Studies of the role of the liver in human carbohy-drate metabolism by the venous catheter technic. I. Normal subjects under fasting conditions and following the injection of glucose. J Clin Invest 1949;28:238-244
62. Booth DA BT: Hunger elicited in the rat by a single injection of bovine crystalline insulin. Physiol Behav 1968;3:439-446
127
63. Brownlee M: Glycation products and the pathogenesis of diabetic complications.
Diabetes Care 1992;15:1835-1843
64. Calvert GD, Graham JJ, Mannik T, Wise PH, Yeates RA: Effects of therapy on plasma-high-density-lipoprotein-cholesterol concentration in diabetes mellitus.
Lancet 1978;2:66-68
65. Cambien F, Warnet JM, Eschwege E, Jacqueson A, Richard JL, Rosselin G: Body mass, blood pressure, glucose, and lipids. Does plasma insulin explain their relationships? Arteriosclerosis 1987;7:197-202
66. Campbell IW, Duncan C, Patton NW, Broadhead T, Tucker GT, Woods HF: The ef-fect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus. Diabet Med 1987;4:337-341
67. Campbell PJ, Gerich JE: Impact of obesity on insulin action in volunteers with normal
67. Campbell PJ, Gerich JE: Impact of obesity on insulin action in volunteers with normal