Elsevier

Surgery

Volume 127, Issue 6, June 2000, Pages 687-695
Surgery

Original Communications
Insulin and glucocorticoid-dependent suppression of the IGF-I system in diabetic wounds*,**

https://doi.org/10.1067/msy.2000.105869Get rights and content

Abstract

Background: Growth-promoting polypeptides, including insulin-like growth factor-I (IGF-I), orchestrate different biochemical events that culminate in the restoration of functional integrity of wounded skin. The nonhealing cutaneous wound is a well-documented phenomenon in experimental and clinical diabetes. Accordingly, we undertook this study to ascertain whether diabetes impairs the healing process by suppressing the wound microenvironmental IGF-I system (eg, IGF-I; IGF-I receptor [IGF-I R]; and IGF-I binding protein [IGF-BP3]). Methods: The induction of diabetes was achieved by the intravenous injection of streptozotocin at a dose of 55 mg/kg. Subcutaneously implanted polyvinyl alcohol sponge and stainless steel mesh chamber models were used to study wound healing. Nondiabetic and diabetic animals received, respectively, subcutaneous 30-day time-release pellets of glucocorticoid (200 mg) and mifepristone (RU-486, 25 mg). Corresponding control animals received placebo pellets. Polyvinyl alcohol sponge and wound fluid expression of the IGF-I system were evaluated by using ligand blotting, radioimmunoassay, and reverse transcriptase polymerase chain reaction-based techniques. Results: Polyvinyl alcohol sponge contents of messenger RNA (mRNA) transcripts encoding for IGF-I, IGF-I R, and IGF-BP3 were reduced in diabetic and glucocorticoid-treated control animals. A similar pattern of changes in protein levels of IGF-I and IGF-BP3 occurred in wound fluid collected from these animals. Partial normalization of the associated hyperglycemic and hypercortisolemic states of diabetes with insulin (hyperglycemia) and the glucocorticoid receptor blocker RU-486 (hypercortisolemia) ameliorated the diabetes-related decrease in the IGF-I system during wound healing. Conclusions: The current data, together with data garnered from the literature, support the concept that the state of hypercortisolemia in diabetes mellitus impairs the healing process, at least in part, by suppressing the wound microenvironmental IGF-I system. Confirmation regarding this premise awaits further investigation. (Surgery 2000;127:687-95.)

Section snippets

Animals

Adult Wistar male rats (Kuwait University breeding colony) weighing 175 to 220 g at the beginning of the experiment were used. The rats were housed in groups of 5 in plastic cages in artificial lighting with a fixed 12-hour light-dark cycle. The ambient temperature was kept at 22°C, and the rats had free access to standard laboratory food and tap water. The study protocol was approved by the institutional animal investigation committee.

Diabetes induction and insulin treatment

Diabetes was induced in overnight-fasted rats by an

Biochemical and physical parameters

Five to 7 days after STZ injection, animals taken from various experimental groups—including vehicle-diabetic, insulin-diabetic, and RU-486-diabetic—were initially matched with regard to plasma levels of glucose (480 ± 35/100 mL ), insulin (0.90 ± 0.2 μU/mL), and hydroxybutyrate (1.35 ± 0.4 mmol/L). These indexes are commonly used as indicators of the severity of diabetes. Physical and biochemical evaluation of animals in various experimental groups revealed that the gain in body weight of the

Discussion

IGF-I alone or in connection with other growth-promoting polypeptides orchestrates different biochemical events that culminate in the restoration of functional integrity of wounded skin. Wound healing potential is diminished as a function of diabetes. Identification of the biochemical abnormalities responsible for the development of this phenomenon has remained a challenge for decades, and its is still not known whether nonhealing, cutaneous, diabetic wounds can be reversed in a clinical

Acknowledgements

We thank Ms Sabah Wahid, Dr Saju Abraham, and Dr Thameem Farook for their technical assistance and Prof C. W. T. Pilcher for his helpful comments and suggestions.

References (65)

  • MS Bitar et al.

    Attenuation of IGF-I antinociceptive action and a reduction in spinal cord gene expression of its receptor in experimental diabetes

    Pain

    (1998)
  • MS Bitar et al.

    Diabetes-induced suppression of IGF-I and its receptor mRNA levels in rat superior cervical ganglia

    Diabetes Res Clin Pract

    (1997)
  • M Roy et al.

    Hypothalamic-pituitary-adrenal axis dysregulation among diabetic outpatients

    Psychol Res

    (1990)
  • SJ Chittenden et al.

    Microangiopathy in diabetes mellitus: causes, prevention and treatment

    Diabetes Res

    (1991)
  • EW Jones et al.

    A clinico-pathological study of diabetic foot ulcers

    Diabet Med

    (1987)
  • RE Pecoraro et al.

    Pathways to diabetic limb amputation: basis for prevention

    Diabetes Care

    (1990)
  • MK Prokash et al.

    Studies in wound healing in experimental diabetes

    Int Surg

    (1974)
  • WH Goodson et al.

    Wound healing and the diabetic patients

    Surg Gynecol Obstet

    (1979)
  • DK Yue et al.

    Effects of experimental diabetes uremia and malnutrition on wound healing

    Diabetes

    (1987)
  • TJ Fahey et al.

    Diabetes impairs the late inflammatory response to wound healing

    J Surg Res

    (1991)
  • MS. Bitar

    Glucocorticoid dynamics and impaired wound healing in diabetes mellitus

    Am J Pathol

    (1998)
  • JF. McMurray

    Wound healing with diabetes mellitus

    Surg Clin North Am

    (1984)
  • RL Bashey et al.

    Stimulation of collagen synthesis in embryonic chick skin by insulin

    Connect Tissue Res

    (1972)
  • L Mikkonen et al.

    Effect of thyroid hormones, somatotrophin, insulin and corticosteroids on synthesis of collagen in granulation tissue both in vivo and in vitro

    Acta Endocrinol

    (1966)
  • SP. Rosenthal

    Acceleration of primary wound healing by insulin

    Arch Surg

    (1968)
  • TT Andreassen et al.

    The influence of experimental diabetes and insulin treatment on the biochemical properties of rat skin incisional wounds

    Acta Chir Scand

    (1987)
  • JD Bagdade et al.

    Reversible abnormalities in phagocytic function in poorly controlled diabetic patients

    Am J Med Sci

    (1972)
  • N. Sandberg

    Time relationship between administration of cortisone and wound healing in rats

    Acta Chir Scand

    (1964)
  • P Goforth et al.

    Effects of steroids on wound healing: a review of the literature

    J Foot Surg

    (1980)
  • JJ McNamara et al.

    Effect of short term pharmacological doses of adrenocorticosteroid therapy on wound healing

    Ann Surg

    (1968)
  • TK Hunt et al.

    Effect of vitamin A on reversing the inhibitory effect of corticosterone on healing of open wounds in animals and men

    Ann Surg

    (1969)
  • AJ D'Ercole et al.

    Tissue concentrations of somatomedin C: further evidence for multiple sites of synthesis and paracrine or autocrine mechanism of action

    Proc Natl Acad Sci U S A

    (1984)
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    *

    Supported by Kuwait University Grant MR033.

    **

    Reprint requests: Prof Milad S. Bitar, Department of Pharmacology, Faculty of Medicine, PO Box 24923, 13110 Safat, Kuwait.

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