Abstract
The efficacy and safety of the preprandial injection of insulin lispro was compared
with the oral administration of glibenclamide in patients with early type 2 diabetes.
In this open-label, multicenter study, 143 patients with a glucagon-stimulated increase
in C-peptide of at least 0.4 nmol/L were randomized to receive preprandial insulin
lispro (LP) or glibenclamide (GB) for 26 weeks. Seventy-five patients received LP
(51 male/24 female; age 40 to 70 years, duration of diabetes 4.4 ± 2.9 years) and
68 patients received GB (39 male/29 female; age 39 to 70 years; duration of diabetes
4.3 ± 3.4 years). After 12 weeks, mean 90 minute blood glucose excursions were 0.9
± 1.0 mmol/L for LP and 1.8 ± 1.2 mmol/L for GB (p < 0.0001). After 24 weeks, mean
blood glucose excursions were 1.0 ± 1.1 mmol/L for LP and 1.7 ± 1.2 mmol/L for GB
(p = 0.002). Body weight decreased slightly from 87.2 ± 2.3 to 86.5 ± 12.2 kg in the
LP group and increased from 84.1 ± 13.7 to 84.4 ± 13.3 kg in the GB group. LP versus
GB induced changes from baseline to endpoint in fasting C-peptide (nmol/L), proinsulin
and insulin levels (pmol/L) were - 0.2 ± 0.4 versus - 0.1 ± 0.6 (p = 0.04), - 11.2
± 26.0 versus - 1.1 ± 17.3 (p = 0.03), and - 27.8 ± 147.4 versus + 32.6 ± 286.2 (not
significant), respectively. HbA1c at baseline was 7.5 ± 1.0 % for LP and 7.7 ± 1.2 % for GB and did not change significantly
in either group during the investigation. No significant difference was observed between
the groups with respect to hypoglycemic episodes. Treatment with LP improved postprandial
blood glucose control more than GB without increasing body weight or hypoglycemic
episodes. In addition, use of LP was associated with a decrease in fasting C-peptide
and proinsulin levels, suggesting a potential down regulation of endogenous insulin
production and improved proinsulin processing efficiency.
Key words
Early diabetes type 2 - Insulin lispro - Glibenclamide - C-peptide - Proinsulin -
HbA1c
References
- 1
Agardh C D, Nilsson-Ehle P, Schersten B.
Improvement of the plasma lipoprotein pattern after institution of insulin treatment
in diabetes mellitus.
Diabetes Care.
1982;
5
322-325
- 2
Andrews W J, Vasquez B, Nagulesparan M, Klimes I, Foley J, Unger R, Reaven G M.
Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin
action and secretion that are maintained for two weeks after insulin withdrawal.
Diabetes.
1984;
33
634-642
- 3
Assert R, Scherk G, Bumbure A, Pirags V, Schatz H, Pfeiffer A F.
Regulation of protein kinase C by short term hyperglycaemia in human platelets in
vivo and in vitro.
Diabetologia.
2001;
44
188-195
- 4
Ayo S H, Radnik R, Garoni J A, Troyer D A, Kreisberg J I.
High glucose increases diacylglycerol mass and activates protein kinase C in mesangial
cell cultures.
Am J Physiol.
1991;
261
F571-F577
- 5
Barrett-Connor E, Ferrara A.
Isolated postchallenge hyperglycemia and the risk of fatal cardiovascular disease
in older women and men. The Rancho Bernardo Study.
Diabetes Care.
1998;
21
1236-1239
- 6
Bastyr III E J, Johnson M E, Trautmann M E, Anderson Jr. J H.
Vignati L. Insulin lispro in the treatment of patients with type 2 diabetes mellitus
after oral agent failure.
Clin Ther.
1999;
21
1703-1714
- 7
Bowsher R R, Wolny J D, Frank B H.
A rapid and sensitive radioimmunoassay for the measurement of proinsulin in human
serum.
Diabetes.
1992;
41
1084-1090
- 8
Bruce D G, Chisholm D J, Storlien L H, Borkman M, Kraegen E W.
Meal-time intranasal insulin delivery in type 2 diabetes.
Diabet Med.
1991;
8
366-370
- 9
Bruce D G, Chisholm D J, Storlien L H, Kraegen E W.
Physiological importance of deficiency in early prandial insulin secretion in non-insulin-dependent
diabetes.
Diabetes.
1988;
37
736-744
- 10
Bruttomesso D, Pianta A, Mari A, Valerio A, Marescotti M C, Avogaro A, Tiengo A, Del
Prato S.
Restoration of early rise in plasma insulin levels improves the glucose tolerance
of type 2 diabetic patients.
Diabetes.
1999;
48
99-105
- 11
Calles-Escandon J, Robbins D C.
Loss of early phase of insulin release in humans impairs glucose tolerance and blunts
thermic effect of glucose.
Diabetes.
1987;
36
1167-1172
- 12
Ceriello A.
Acute hyperglycaemia and oxidative stress generation.
Diabet Med.
1997;
14 (Suppl 3)
S45-S49
- 13
Ceriello A, Falleti E, Bortolotti N, Motz E, Cavarape A, Russo A, Gonano F, Bartoli E.
Increased circulating intercellular adhesion molecule-1 levels in type II diabetic
patients: the possible role of metabolic control and oxidative stress.
Metabolism.
1996 a;
45
498-501
- 14
Ceriello A, Giacomello R, Stel G, Motz E, Taboga C, Tonutti L, Pirisi M, Falleti E,
Bartoli E.
Hyperglycemia-induced thrombin formation in diabetes. The possible role of oxidative
stress.
Diabetes.
1995;
44
924-928
- 15
Ceriello A, Taboga C, Tonutti L, Giacomello R, Stel L, Motz E, Pirisi M.
Post-meal coagulation activation in diabetes mellitus: the effect of acarbose.
Diabetologia.
1996 b;
39
469-473
- 16
de Vegt F, Dekker J M, Ruhe H G, Stehouwer C D, Nijpels G, Bouter L M, Heine R J.
Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn
population: the Hoorn Study.
Diabetologia.
1999;
42
926-931
- 17
DeFronzo R A.
The effect of insulin on renal sodium metabolism. A review with clinical implications.
Diabetologia.
1981;
21
165-171
- 18
Del Prato S, Tiengo A.
The importance of first-phase insulin secretion: implications for the therapy of type
2 diabetes mellitus.
Diabetes Metab Res Rev.
2001;
17
164-174
- 19
Feinglos M N, Thacker C H, English J, Bethel M A, Lane J D.
Modification of postprandial hyperglycemia with insulin lispro improves glucose control
in patients with type 2 diabetes.
Diabetes Care.
1997;
20
1539-1542
- 20
Garvey W T, Olefsky J M, Griffin J, Hamman R F, Kolterman O G.
The effect of insulin treatment on insulin secretion and insulin action in type II
diabetes mellitus.
Diabetes.
1985;
34
222-234
- 21
Gerich J E.
Is reduced first-phase insulin release the earliest detectable abnormality in individuals
destined to develop type 2 diabetes?.
Diabetes.
2002;
51 (Suppl 1)
S117-S121
- 22
Hanefeld M, Fischer S, Julius S, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch H J,
Lindner J.
Risk factors for myocardial infarction and death in newly detected NIDDM: the diabetes
intervention study, 11 year follow up.
Diabetologia.
1996;
39
1577-1583
- 23
Hanefeld M, Koehler C, Schaper F, Fuecker K, Henkel E, Temelkova-Kurktschiev T.
Postprandial plasma glucose is an independent risk factor for increased carotid intima-media
thickness in non-diabetic individuals.
Atherosclerosis.
1999;
144
229-235
- 24
Hanley A J, McKeown-Eyssen G, Harris S B, Hegele R A, Wolever T M, Kwan J, Connelly P W,
Zinman B.
Cross-sectional and prospective associations between proinsulin and cardiovascular
disease risk factors in a population experiencing rapid cultural transition.
Diabetes Care.
2001;
24
1240-1247
- 25
Heinemann L, Heise T, Wahl L C, Trautmann M E, Ampudia J, Starke A A, Berger M.
Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using
the rapid acting insulin analogue [Lys(B28), Pro(B29)] human insulin.
Diabet Med.
1996;
13
625-629
- 26
Hosker J P, Burnett M A, Matthews D R, Turner R C.
Suppression of insulin secretion by falling plasma glucose levels is impaired in type
2 diabetes.
Diabet Med.
1988;
5
856-860
- 27
Howey D C, Bowsher R R, Brunelle R L, Woodworth J R.
[Lys(B28), Pro(B29)]-human insulin.
Diabetes.
1994;
43
396-402
- 28
Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E.
Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients
by transient intensive insulin treatment.
Diabetes Care.
1997;
20
1353-1356
- 29
Jain S K, Nagi D K, Slavin B M, Lumb P J, Yudkin J S.
Insulin therapy in type 2 diabetic subjects suppresses plasminogen activator inhibitor
(PAI-1) activity and proinsulin-like molecules independently of glycaemic control.
Diabet Med.
1993;
10
27-32
- 30
Kawamori R, Bando K, Yamasaki Y, Kubota M, Watarai T, Iwama N, Shichiri M, Kamada T.
Fasting plus prandial insulin supplements improve insulin secretory ability in NIDDM
subjects.
Diabetes Care.
1989;
12
680-685
- 31
Kraegen E W, Young J D, George E P, Lazarus L.
Oscillations in blood glucose and insulin after oral glucose.
Horm Metab Res.
1972;
4
409-413
- 32
Lefebvre P, Scheen A J.
The postprandial state and risk of cardiovascular disease.
Diabet Med.
1998;
15
S63-S68
- 33
Leibowitz G, Cerasi E.
Sulphonylurea treatment of NIDDM patients with cardiovascular disease: a mixed blessing?.
Diabetologia.
1996;
39
503-514
- 34
Malmberg K.
Prospective randomised study of intensive insulin treatment on long term survival
after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes
Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group.
BMJ.
1997;
314
1512-1515
- 35
Malmberg K, Ryden L, Hamsten A, Herlitz J, Waldenstrom A, Wedel H.
Effects of insulin treatment on cause-specific one-year mortality and morbidity in
diabetic patients with acute myocardial infarction. DIGAMI Study Group. Diabetes Insulin-Glucose
in Acute Myocardial Infarction.
Eur Heart J.
1996;
17
1337-1344
- 36
Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J.
Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia
in NIDDM.
Diabetes.
1990;
39
1381-1390
- 37
Muhlhauser I, Sawicki P T, Berger M.
Possible risk of sulfonylureas in the treatment of non-insulin-dependent diabetes
mellitus and coronary artery disease.
Diabetologia.
1997;
40
1492-1493
- 38
Nagi D K, Hendra T J, Ryle A J, Cooper T M, Temple R C, Clark P M, Schneider A E,
Hales C N, Yudkin J S.
The relationships of concentrations of insulin, intact proinsulin and 32 - 33 split
proinsulin with cardiovascular risk factors in type 2 (non-insulin-dependent) diabetic
subjects [see comments].
Diabetologia.
1990;
33
532-537
- 39
Owens D R, Jones M K, Hayes T M, Heding L G, Alberti K G, Home P D, Burrin J M.
Comparative study of subcutaneous, intramuscular, and intravenous administration of
human insulin.
Lancet.
1981;
2
118-122
- 40
Panahloo A, Mohamed-Ali V, Andres C, Denver A E, Yudkin J S.
Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis
in type II diabetes.
Metabolism.
1998;
47
637-643
- 41
Paterson K R, Wilson M, Kesson C M, Buchan M, Roberts M, Reith S B, Davidson E.
Comparison of basal and prandial insulin therapy in patients with secondary failure
of sulphonylurea therapy.
Diabet Med.
1991;
8
40-43
- 42
Poitout V, Robertson R P.
An integrated view of beta-cell dysfunction in type-II diabetes.
Annu Rev Med.
1996;
47
69-83
- 43
Polonsky K S.
Non-insulin dependent diabetes mellitus: a genetically programmed failure of the beta
cell to compensate for insulin resistance.
N Engl J Med.
1996;
334
777-783
- 44
Reaven G M.
Banting lecture 1988. Role of insulin resistance in human disease.
Diabetes.
1988;
37
1595-1607
- 45
Robbins D C, Jaspan J, Vasquez B, Van Cauter E.
Biphasic patterns of peripheral insulin and glucose levels after lunch in normal subjects.
Diabetes Care.
1987;
10
293-299
- 46
Shaw J E, Hodge A M, de Courten M, Chitson P, Zimmet P Z.
Isolated post-challenge hyperglycaemia confirmed as a risk factor for mortality [published
erratum appears in Diabetologia 1999; 42: 1444].
Diabetologia.
1999;
42
1050-1054
- 47
Temelkova-Kurktschiev T S, Koehler C, Leonhardt W, Schaper F, Henkel E, Siegert G,
Hanefeld M.
Increased intima-medial thickness in newly detected type 2 diabetes: risk factors.
Diabetes Care.
1999;
22
333-338
- 48
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A.
Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired
fasting glucose.
Diabetes Care.
1999;
22
920-924
- 49
Torlone E, Fanelli C, Rambotti A M, Kassi G, Modarelli F, Di Vincenzo A, Epifano L,
Ciofetta M, Pampanelli S, Brunetti P.
Pharmacokinetics, pharmacodynamics and glucose counterregulation following subcutaneous
injection of the monomeric insulin analogue [Lys(B28), Pro(B29)] in IDDM.
Diabetologia.
1994;
37
713-720
- 50
Turner R C, McCarthy S T, Holman R R, Harris E.
Beta-cell function improved by supplementing basal insulin secretion in mild diabetes.
Br Med J.
1976;
1
1252-1254
- 51
Yoshioka N, Kuzuya T, Matsuda A, Taniguchi M, Iwamoto Y.
Serum proinsulin levels at fasting and after oral glucose load in patients with type
2 (non-insulin-dependent) diabetes mellitus.
Diabetologia.
1988;
31
355-360
- 52
Yudkin J S.
Circulating proinsulin-like molecules.
J Diabetes Complications.
1993;
7
113-123
- 53
Yudkin J S, May M, Elwood P, Yarnell J W, Greenwood R, Davey S G.
Concentrations of proinsulin-like molecules predict coronary heart disease risk independently
of insulin: prospective data from the Caerphilly Study.
Diabetologia.
2002;
45
327-336
Priv. Doz. Dr. Thomas Forst
Institute for Clinical Research and Development
Parcusstraße 8
55116 Mainz
Germany
Email: Thomasf@ikfe.de