Abstract
Aims: This study set out to define relationships between changes in plasma leptin and changes in body weight, plasma insulin and blood glucose control during a 12-month crossover study of once-daily Ultratard or twice-daily Insulatard insulin.
Patients and Methods: Fasting plasma leptin and insulin were measured during a multicentre cross-over study involving 60 subjects with type 2 diabetes (fasting glucose > 8 mM). After a 2-month run-in, there were two 6-month periods of treatment with Insulatard or Ultratard insulin.
Results: Mean plasma leptin increased significantly in both groups after insulin therapy was instigated (12.8 ± 8.1 to 22.9 ± 13.1 ng/ml in the Insulatard group; 12.1 ± 7.2 to 19.2 ± 12.3 ng/ml in the Ultratard group). Weight also increased significantly in both groups (82.4 ± 14.3 kg to 88.8 ± 14.3 kg and 82.2 ± 15.3 kg to 85.3 ± 15.2 kg respectively). The increase in plasma leptin correlated well with the increase in weight (R = 0.416, p = 0.001), and this correlation continued after the crossover point. Plasma leptin correlated with BMI throughout the study (R = 0.540, p = 0.000).
Conclusion: The sustained rise in body weight despite a substantial increase in plasma leptin suggests that either resistance to the hypothalamic action of leptin develops when insulin therapy is begun in type 2 diabetes, or that resetting of the set point for body weight occurs such that a larger body mass is tolerated for a given level of plasma leptin.
Key words
Leptin - Type 2 Diabetes - Insulin Treatment - Obesity - Appetite
References
-
1
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M.
Positional cloning of the mouse obese gene and its human homologue.
Nature.
1994;
372
425-432
-
2
Pelleymounter M A, Cullen M J, Baker M B, Hecht R, Winters D, Boone T, Collins F.
Effects of the obese gene product on body weight regulation in ob/ob mice.
Science.
1995;
269
540-543
-
3
Campfield L A, Smith F J, Guisez Y, Devos R, Burn P.
Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks.
Science.
1995;
269
546-549
-
4
Levin N, Nelson C, Gurney A, Vandlen R, de Sauvage F.
Decreased food intake does not completely account for adiposity reduction after ob protein infusion.
Proc Natl Acad Sci USA.
1996;
93
1726-1730
-
5
Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Birley S K, Friedman J M.
Weight reducing effects of the plasma protein encoded by the obese gene.
Science.
1995;
269
543-546
-
6
Rentsch J, Levens N, Chiesi M.
Recombinant ob-gene product reduces food intake in fasted mice.
Biochemical Biophysical Research Communications.
1995;
214
131-136
-
7
Lawrence V J, Coppack S W.
The endocrine function of the fat cell - regulation by the sympathetic nervous system.
Horm Metab Res.
2000;
32
453-467
-
8
Peacock I, Tattersall R B.
The difficult choice of treatment for poorly controlled maturity onset diabetes:tablets or insulin.
BMJ.
1984;
288
1956-1959
-
9
Turner R C.
UK Prospective Diabetes Study II. Reduction in HbA1c with basal insulin supplement sulphonylurea or biguanide therapy in maturity onset diabetes.
Diabetes.
1985;
61
32-36
-
10
Taylor R, Davies R, Fox C, Sampson M, Weaver J U, Wood L.
Appropriate insulin treatment for Type 2 diabetes: a multicentre, randomised crossover study.
Diabetes Care.
2000;
23
1612-1618
-
11 Home P D. Insulin therapy. In: Alberti KGMM, Zimmet P, DeFronzo RA (eds) Internatioal Textbook of Diabetes Mellitus, 2nd Ed., Vol. One. Wiley 1997: 899-928
-
12
Yki-Jarvinen H, Kauppila M, Kujansyuu E, Lahti J, Marjanen T, Niskanen L, Rajala S, Ryysy L, Salo S, Seppala P, Tulokas T, Viikari J, Karjalainen J, Taskinen M-R.
Comparison of insulin regimens in patients with non-insulin dependent diabetes mellitus.
N Eng J Med.
1992;
327
1426-1433
-
13
González-Ortiz M, Martíez-Abundis E, Balcázar-Muñoz B R.
Serum leptin concentrations in young insulin-sensitive and insulin-resistant volunteers.
Horm Metab Res.
2000;
32
273-276
-
14
Zavaroni I, Gasparini P, Barilli A I, Massironi P, Campanini C, Carantoni M, Delsignore R, Reaven G M.
Comparison of fasting plasma leptin concentrations in healthy subjects with high and low plasma insulin.
Metabolism.
2000;
49
499-502
-
15
Malmstrom R, Taskinen M R, Karonen S L, Yki-Jarvinen H.
Insulin increases plasma leptin concentrations in normal subjects and in patients with NIDDM.
Diabetologia.
1996;
39
993-996
-
16
Wellhoener P, Fruehwald-Schultes B, Kern W, Dantz D, Kerner W, Born J, Fehm H L, Peters A.
Glucose metabolism rather than insulin is a main determinant of leptin secretion in humans.
J Clin Endocrinol Metab.
2000;
85 (3)
1267-1271
-
17
Wang J, Liu R, Hawkins M, Barzilai N, Rossetti L.
A nutient-sensing pathway regulates leptin gene expression in muscle and fat.
Nature.
1998;
393
684-688
-
18
Hathout E H, Sharkey J, Racine M, Ahn D, Mace J W, Saad M F.
Changes in plasma leptin during the treatment of diabetic ketoacidosis.
J Clin Endocrinol Metab.
1999;
84 (12)
4545-4548
-
19
Groop L, Franssila-Kallunki A, Ekstrand A, Saloranta C, Schalin C, Eriksson J.
Different effects of insulin and oral antidiabetic agents on glucose and energy metabolism in type 2 (non-insulin dependent) diabetes mellitus.
Diabetologia.
1989;
32
599-605
-
20
El-Haschimi K, Pierroz D D, Hileman S M, Bjorbaek C, Flier J S.
Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity.
J Clin Invest.
2000;
105 (12)
1827-1832
-
21
Moriya M, Okumura T, Takahashi N, Yamagata K, Motomura W, Kohgo Y.
An inverse correlation between plasma leptin levels and hemogloblin AIc in patients with non-insulin dependant diabetes mellitus.
Diabetes Research and Clinical Practice.
1999;
43
187-191
-
22
Shoji T, Nishizawa Y, Emoto M. et al .
Renal function and insulin resistance as determinants of plasma leptin levels in patients with NIDDM.
Diabetologia.
1997;
40
676-679
-
23
Widjaja A, Stratton I M, Horn R, Holman R P, Turner R, Brabant G.
UKPDS: Plasma leptin, obesity, and plasma insulin in Type 2 diabetic subjects.
J Clin Endocrinol Metab.
1997;
82 (2)
654-657
Dr. Peter E. Carey
Department of Medicine · The Medical School
Framlington Place · Newcastle-upon-Tyne · NE2 4HH · UK
Phone: + 44 (191) 2325131
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Email: p.e.carey@ncl.ac.uk
