In a post hoc analysis of two randomized controlled trials in patients with type 2 diabetes mellitus, Aas and colleagues (1) found a correlation between a 10% increase in plasma leptin concentrations during baseline hyperinsulinemic (1.0 mU•kg-1•min-1) euglycemic clamps and weight gain after one year of treatment with insulin (which raised plasma insulin concentrations by one-third). Because the increase in leptin occurred before the increase in body weight, the authors suggested that increased insulin per se, and not increased fat mass, was responsible for the increase in leptin levels (1).
However, unpublished data from our studies of 13 (2) and 14 (3) healthy humans revealed that physiological, as opposed to pharmacological (1, 4), hyperinsulinemia does not raise leptin concentrations. When plasma insulin concentrations were raised from 24 ± 6 pmol/L (4 ± 1 μU/mL) to 84 ± 12 pmol/L (14 ± 2 μU/mL) by infusion of insulin in a dose of 0.2 mU•kg-1•min-1, plasma leptin concentrations (measured with the Linco Radioimmunoassay, Temecula, CA) declined from 776 ± 160 nmol/L (9.7 ± 2.0 ng/mL) at 0 min to 632 ± 120 nmol/L (7.9 ± 1.5 ng/mL) at 240 min (P = 0.0077) even though that ultimately drove plasma glucose concentrations down to subphysiological levels and therefore raised plasma epinephrine, pancreatic polypeptide, glucagon, cortisol and growth hormone levels (2). Similar plasma leptin concentrations – 680 ± 136 nmol/L (8.5 ± 1.7 ng/mL) to 552 ± 112 nmol/L (6.9 ± 1.4 ng/mL) over 240 min (P = 0.0306) – were observed during saline infusions with insulin levels if 24 ± 6 pmol/L (4 ± 1 μU/mL) (2). The same plasma leptin concentration patterns occurred during suppression of insulin levels to 12 ± 0 pmol/L (2 ± 0 μU/mL) by intravenous infusion of octreotide and during octreotide plus insulin (0.1 mU•kg-1•min-1) infusion that raised insulin levels to 48 ± 6 pmol/L (8 ± 1 μU/mL) (P = 0.0042 and P = 0.0140 for leptin respectively) (3). (Plasma ghrelin concentrations were also unaltered by these variations in insulin levels but were suppressed by octreotide.)
Thus, in contrast to pharmacological hyperinsulinemia (1, 4, 5), physiological hyperinsulinemia does not raise leptin concentrations. That is true even when physiological hyperinsulinemia lowers plasma glucose concentrations and activates the sympathoadrenal (epinephrine) and parasympathetic (pancreatic polypeptide) nervous systems, pancreatic α-cells (glucagon), adrenal cortices (cortisol) and pituitary
somatotrophs (growth hormone) (2) as well as when these are not activated (3).
References
1. Aas A-M, Hanssen KF, Berg JP, Thorsby PM, Birkeland KI 2009 Insulin-stimulated increase in serum leptin levels precedes and correlates with weight gain during insulin therapy in type 2 diabetes. J Clin Endocrinol Metab 94:2900-2906
2. Breckenridge SM, Raju B, Arbelaez AM, Patterson BW, Cooperberg BA, Cryer PE 2007 Basal insulin, glucagon and growth hormone replacement. Am J Physiol Endocrinol Metab 293:E1303-E1310
3. Breckenridge SM, Cooperberg BA, Arbelaez AM, Patterson BW, Cryer PE 2007 Glucagon, in concert with insulin, supports the postabsorptive plasma glucose concentration in humans. Diabetes 56:2442-2448
4. Utriainen T, Malmström R, Mäkimattila S, Yki-Järvinen H 1996 Supraphysio¬logical hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes 45:1364-1366
5. Jackson MB, Ahima RS 2006 Neuroendocrine and metabolic effects of adipocyte-derived hormones. Clin Sci (Lond) 110:143-152
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