Benefits of insulin treatment in cancer cachexia

[Dr.Vad]

Clin Cancer Res. 2007 May 1;13(9):2699-706.

Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning.

Lundholm K, Korner U, Gunnebo L, Sixt-Ammilon P, Fouladiun M, Daneryd P, Bosaeus I.

Departments of Surgery and Clinical Nutrition, Sahlgrenska University Hospital, Goteborg University, Goteborg, Sweden.

PURPOSE: The present study was designed to evaluate whether daily insulin treatment for weight-losing cancer patients attenuates the progression of cancer cachexia and improves metabolism and physical functioning in palliative care. EXPERIMENTAL DESIGN: One hundred and thirty-eight unselected patients with mainly advanced gastrointestinal malignancy were randomized to receive insulin (0.11 +/- 0.05 units/kg/d) plus best available palliative support [anti-inflammatory treatment (indomethacin), prevention of anemia (recombinant erythropoietin), and specialized nutritional care (oral supplements + home parenteral nutrition)] according to individual needs. Control patients received the best available palliative support according to the same principles. Health-related quality of life, food intake, resting energy expenditure, body composition, exercise capacity, metabolic efficiency during exercise, and spontaneous daily physical activity as well as blood tests were evaluated during follow-up (30-824 days) according to intention to treat. RESULTS: Patient characteristics at randomizations were almost identical in study and control groups. Insulin treatment for 193 +/- 139 days (mean +/- SD) significantly stimulated carbohydrate intake, decreased serum-free fatty acids, increased whole body fat, particularly in trunk and leg compartments, whereas fat-free lean tissue mass was unaffected. Insulin treatment improved metabolic efficiency during exercise, but did not increase maximum exercise capacity and spontaneous physical activity. Tumor markers in blood (CEA, CA-125, CA 19-9) did not indicate the stimulation of tumor growth by insulin; a conclusion also supported by improved survival of insulin-treated patients compared with controls [study patients, 224 ± 163 days; controls, 175 ± 148 days (mean ± SD); 181 versus 128 days (median)]. (P < 0.03). CONCLUSION: Insulin is a significant metabolic treatment in multimodal palliation of weight-losing cancer patients.

[Liubov]

Спасибо за статью Вадим Валерьевич! У Вас нет информации назначался ли инсулин при наличии кахексии или для ее профилактики? Были другие исследования в этой области?

Еще вопрос по оценке влияния инсулина на рост опухоли. Насколько я знаю уровень CEA быстро не изменяется. При положительном эффекте лечения, некоторое время уровень CEA может оставаться высоким. Допустим инсулин стимулирует рост опухоли, стабильный уровень CEA не будет индикатором. Ваше мнение?

[Dr.Vad]

Я как бы не очень силен в теме, насколько мне известно инсулин у опухолевых пациентов, теряющих вес, ранее рандомизированно не применялся. Быть может, Вам пригодится фрагмент дискуссии из оригинала?:

Early studies on cachectic cancer patients showed glucose intolerance in combination with altered whole body carbohydrate metabolism (24–28), in which animal work implied that insulin would beneficially overcome some of these problems (29–31). Observations indicated that glucose intolerance might appear early in cancer, even before weight loss and anorexia (32). Glucose intolerance was also observed independently of the presence of tumor tissue (33), indicating hormonal and enzymatic adaptations in host liver, fat (34), and muscles (35). Defective insulin production and increased insulin clearance during feeding may also contribute to glucose intolerance in cancer. However, graded doses of insulin infusions to cancer patients confirmed insulin resistance in glucose homeostasis of peripheral tissues (36), whereas insulin effects on amino acid flux did not indicate resistance (35, 37), which agrees with the findings of insignificant effects on muscle mass by insulin in the present study, although IGF-I had clear-cut effects to protect muscle wasting in experimental tumor bearers (38).

Several of our previous studies on patients with cancer suggested metabolic abnormalities related to insulin (39), both in feeding (26, 40) and fasted states (24). It has been repeatedly emphasized that loss of lean tissue in cancer disease is most important in the progression of cachexia hampering well-being and physical functioning. However, recent analyses on longitudinal measurement of body compositions implied that loss of body fat remained or even progressed despite appropriate caloric intake and stable lean tissue mass (8). Based on this information, it is obvious that additional factors are necessary for the improvement of integrative anabolism in feeding patients with cancer (26). Therefore, it was logical to assume that insulin might have a role in improving anabolism or at least attenuating catabolism during disease progression.

Study and control patients were extremely well balanced regarding clinical characteristics at inclusion. Insulin treatment stimulated carbohydrate intake, although the increase of overall caloric intake did not reach statistical significance. Serum insulin increased over time in study patients, whereas it decreased in control patients. A similar pattern was observed on circulating C-peptide, supporting that exogenous insulin did not counteract endogenous production. Higher serum insulin did not change IGF-I levels, which may explain the dissociated effects by insulin on whole body fat and lean tissue, although it has never been shown that insulin in itself is a major factor to control long-term muscle protein balance in man (37, 41, 42). As expected, serum-free fatty acids decreased significantly following insulin treatment, which was probably translated into significantly improved whole body fat in study patients, particularly in trunk and leg compartments dependent on both increased lipogenesis and decreased lipolysis (24, 26, 40). Observations that lean tissues (protein metabolism) were less affected compared with whole body fat is in line with our previous findings in acute experiments with insulin to normal individuals (41). Interestingly, the overall effects of insulin were translated into increased metabolic efficiency, derived as oxygen consumed per watt produced at maximum work load. This may imply facilitated physical functioning, perhaps due to improved glycogen content and glucose transporting in muscles (43). However, this positive effect was not translated into elevated maximum exercise capacity or increased spontaneous physical activity, which may be more dependent on overall cardiovascular and mental functioning than integrative metabolism. Also, self-reported evaluation of health-related quality of life indicated that positive objective metabolic effects by insulin may not be translated into improved self-scored physical functioning, which agree with previous observations in non–cancer patients (44).

Еще о кахексии при различных заболеваниях и возможные пути ее коррекции рассматриваются в этом доступном обзоре: Cachexia: pathophysiology and clinical relevance

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