GLUTAMINE SUPPLEMENTATION STUDIES
In a study of healthy young males, Iwashita et al. observed that increases in energy expenditure, and both carbohydrate and fat oxidation after glutamine supplementation with a meal may be related to the effect of glutamine on insulin action and glucose disposal (Borel et al. 1998; Iwashita et al.
2006). Awad et al. (2011) also observed blunted postprandial glucose and insulin responses in healthy subjects and hypothesized that glutamine may reduce insulin resistance. This hypothesis
FIGURE 4.1 The catabolic state. Factors regulating catabolic metabolism include hormones and immunological responses. Net metabolic changes occurring after physiological disturbance such as trauma or sepsis, when catabolic and anabolic influences become unbalanced in favor of catabolism, are summarized here. Regulatory and specific organ effects (indicated around the perimeter), particularly in insulin-sensitive tissue, contribute to the net metabolic response (center) and glutamine is important in potentiating several of these effects.
has been supported in clinical situations. For example, in heart surgery patients the use of a preoperative nutriceutic dose of glutamine diminished postoperative stress hyperglycemia (Hissa et al.
2011).
Samocha-Bonet et al. (2011) found T2DM subjects benefited from the reduction of postprandial hyperglycemia mediated by glutamine, and indeed it has been proposed as a potential therapeutic agent for diabetics (Greenfield et al. 2009). In contrast, Chang et al. (2013) found that glutamine given to healthy and T2DM men by intraduodenal infusion did not lower glycemia after glucose, despite stimulating insulin and incretin hormones. Higher glucagon levels (discussed later) were proposed to affect glycemia in this study.
Rat studies confirm the generally observed glucose-lowering effect of glutamine (Opara et al.
1996). Studies in obese or induced Type 1 or 2 diabetic rat or mouse models have found that glutamine (a) decreased plasma glucose and increased circulating insulin (Badole et al. 2013), (b) increased circulating levels of the active form of the incretin hormone glucagon-like peptide 1 (GLP-1) (Badole et al. 2013), and (c) improved glycemic control (Opara et al. 1996; Badole et al.
|
Reference |
Subjects |
Glutamine dose and Control/s |
Effect on Insulin Sensitivity |
Effect on Glycemic Control |
Other Effects of Glutamine |
|
Iwashita et al. (2006) |
10 Healthy males |
1.05 kcal/kg glutamine administered orally or isocaloric amino acid mix containing alanine:glycerine:serine (2:1:0.5) with a mixed meal |
Not measured |
Not measured |
Glutamine increased post-meal energy expenditure by increasing carbohydrate and fat oxidation in early and late post-meal phase, respectively |
|
Awad et al. (2011) |
10 Healthy males |
15 g glutamine administered orally or isocaloric-isovolumetric (50 g carbohydrate OR 36 g carbohydrate + 7 g lipid) drink |
Not measured |
Improved |
Blunted postprandial insulin and glucose responses |
|
Hissa et al. (2011) |
22 Patients with coronary artery occlusion |
250 mL L-alanyl-glutamine dipeptide 20% + saline administered parenterally or saline |
Not measured |
Improved significantly |
|
|
Samocha-Bonet et al. (2011) |
15 T2DM patients |
30 g or 15 g L-glutamine or L-glutamine + sitagliptin in water orally or water |
Not measured |
Improved postprandially |
Increased postprandial insulin response (possibly affecting clearance rather than secretion). Increased GLP-1 concentrations and possibly slowed gastric emptying |
|
Greenfield et al. (2009) |
24 subjects: 8 lean healthy, 8 each obese nondiabetic, and obese with Type 2 diabetes/ impaired glucose tolerance |
30 g glutamine administered orally or water or glucose |
Not measured |
Not measured |
Increased circulating GLP-1 and GIP concentrations Significantly increased circulating plasma insulin concentrations Stimulated glucagon secretion |
|
Chang et al. (2013) |
20 subjects: 10 healthy and 10 with T2DM |
7.5 g or 15 g glutamine administered by intraduodenal infusion or saline |
Not measured |
No effect |
Stimulated incretin hormone (GLP-1, GIP), glucagon, and insulin secretion Increased pyloric motility (Continued) |
Studies of the Effect of Glutamine on Insulin Action and Glycemic Control
TABLE 4.1 (Continued)
|
Reference |
Subjects |
Glutamine dose and Control/s |
Effect on Insulin Sensitivity |
Effect on Glycemic Control |
Other Effects of Glutamine |
|
Opara et al. (1996) |
40 C57BL/6J mice: 10 per diet |
2.87% L-glutamine with a high-fat diet or high fat, low-sucrose diet Low fat or low sucrose, high fat with 3.5% L-alanine |
Not measured |
Prevented or attenuated hyperglycemia |
Prevented or reduced body weight and attenuated hyperinsulinemia |
|
Badole et al. (2013) |
36 Streptozotocin- induced diabetic rats |
250, 500, or 1000 mg/kg/day L-glutamine or distilled water for 8 weeks |
Not measured |
Significant reduction in plasma glucose and glycosylated hemoglobin |
500 and 1000 mg/kg doses reduced food intake and body weight compared to diabetic controls, significantly decreased plasma cholesterol, triglycerides, VLDL, and LDL; increased HDL, active GLP-1, plasma and pancreatic insulin levels, and endogenous liver antioxidants compared to diabetic control. Sitagliptin 5 mg/kg/ day had a similar effect |
|
Tsai, Liu et al. (2012) |
28 Type II diabetic rats |
Glutamine as 25% of total amino acid nitrogen replacing casein or casein in a common semi-purified diet for 8 weeks |
Not measured |
No change |
No difference in food intake or body weights compared to diabetic controls Higher total plasma antioxidant capacity Decreased oxidative stress-related gene expression |
|
Tsai et al. (2011) |
27 Type 1 diabetic mice |
Glutamine as 25% of total amino acid nitrogen or casein in a common semi-purified diet for 6 weeks |
Not measured |
No change |
Leukocyte adhesion may be reduced; Reduced neutrophil infiltration in the liver Reduced nitrotyrosine (marker for oxidative damage to proteins) in organs Increased GSH:GSSG ratio |
|
Borel et al. (1998) |
5 dogs |
0.72 mM/kg/hr glutamine administered by intravenous infusion or saline |
Enhanced responsiveness suggested by results |
Hyperinsulinemic- euglycemic clamp used |
Whole-body glucose production was increased Enhanced insulin-mediated glucose utilization 3-fold compared to changes in glucose production (Continued) |
|
Reference |
Subjects |
Glutamine dose and Control/s |
Effect on Insulin Sensitivity |
Effect on Glycemic Control |
Other Effects of Glutamine |
|
Iwashita et al. (2005) |
6 dogs during, before, and after exercise (hyperinsulinemic, euglycemic clamp conditions) |
12 цМ/kg/min L-glutamine administered by intravenous infusion or saline |
Not measured |
Hyperinsulinemic- euglycemic clamp used |
Increased net hepatic glucose output by 7-fold during exercise |
|
Cui et al. (2013) |
60 patients with colorectal cancer |
0.5 g/kg of 3.4% alanyl-L-glutamine diluted in 8.5% mixed amino acid vehicle, saline OR vehicle administered by intravenous infusion |
Significantly improved in the glutamine group (p < 0.05) measured by HOMA-IR and QUICKI |
Postoperatively increased blood glucose attenuated by glutamine |
Serum TNF-a and free fatty acid concentrations reduced |
|
Bashandy et al. (2013) |
40 patients with cancer |
0.4 g/kg L-alanyl-L-glutamine dipeptide or saline administered by intravenous infusion |
Significantly improved in the glutamine group (p < 0.05) measured by HOMA-IR |
Postoperatively increased blood glucose attenuated by glutamine |
Plasma reduced glutathione levels higher in the glutamine group |
|
Dock-Nashimento et al. (2012) |
48 patients submitted for elective laparoscopic cholecystectomy |
Average 0.77 g/kg (range, 0.61-0.97 g/kg) glutamine with maltodextrine and water administered orally or water only, water with maltodextrine or fasting |
Significantly improved in the glutamine and other intervention groups compared to fasting (p < 0.05) measured by HOMA-IR |
Not measured |
Improved antioxidant defenses (serum glutathione) Reduced proinflammatory cytokines (IL-6, C-reactive protein) No difference in serum triglycerides or VLDL cholesterol Nitrogen balance less negative |
|
Cunha Filho et al. (2011) |
30 children submitted to palatoplasty |
0.5 g/kg L-alanyl-L-glutamine dipeptide or saline |
Not measured |
Improved |
Attenuated inflammatory response (C-reactive protein, but not IL-6) |
(Continued)
Studies of the Effect of Glutamine on Insulin Action and Glycemic Control
TABLE 4.1 (Continued)
|
Reference |
Subjects |
Glutamine dose and Control/s |
Effect on Insulin Sensitivity |
Effect on Glycemic Control |
Other Effects of Glutamine |
|
Bakalar et al. (2006) |
40 multiple trauma patients |
0.4 g/kg/day L-analyl-glutamine (parenteral) + 1.1 g/kg/day mixed amino acids (parenteral or enteral) or balanced amino acid solution (1.5 g/ kg/day parenteral or enteral) |
Prevented insulin resistance as seen in control group |
Lower glycemia in glutamine group |
Higher oxidation of carbohydrates rather than lipids Lower C-peptide plasma concentration on Day 8 indicating reduced insulin expression compared to controls Improved insulin-mediated glucose disposal |
|
Dechelotte et al. (2006) |
complicated surgery (65), or pancreatitis (11) |
0.5 g/kg L-alanyl-L-glutamine dipeptide/day with total parenteral nutrition or isocaloric, isonitrogenous L-alanine + L-proline with total parenteral nutrition |
Not measured |
Less frequent hyperglycemic events amongst glutamine patients |
Lower infection rate and incidence of pneumonia (both p < 0.05) Fewer patients required insulin |
|
Grau et al. (2011) |
127 ICU patients requiring parenteral nutrition for 5-9 days |
0.5 g/kg L-alanyl-L-glutamine dipeptide/day with total parenteral nutrition or isonitrogenous, isocaloric total parenteral nutrition |
Not measured |
Improved |
A 54% reduction in the amount of insulin required for the same levels of glycemia Less pneumonia per days of mechanical ventilation (p = 0.02) Less urinary tract infections per days of urinary catheter (p = 0.04) |
|
Duska et al. (2008) |
30 multiple-trauma patients |
0.3 g/kg L-alanyl-L-glutamine dipeptide/day with total parenteral nutrition or isonitrogenous, isocaloric total parenteral nutrition |
Worsened in the growth hormone + glutamine group, improved in both glutamine and control groups |
Not measured |
Nitrogen economy was improved with growth hormone plus glutamine |
2013) as well as potentially improving insulin sensitivity due to a reduction of oxidative stress (Tsai et al. 2011; Tsai, Liu et al. 2012; Tsai, Yeh et al. 2012; Badole et al. 2013).
Likewise, in canine models, glutamine was shown to enhance insulin-mediated glucose utilization but blunt insulin action on inhibition of glucose production both at rest as well as during and post-exercise (Iwashita et al. 2005). Insulin secretion is usually low post-exercise, but the glutamine effects persisted even upon application of a hyperinsulinemic-euglycemic clamp (Iwashita et al. 2006).
Several randomized controlled trials have shown that glutamine delivered by the oral or parenteral route can improve insulin resistance and glycemic control in surgical (Cunha Filho et al. 2011; Hissa et al. 2011; Dock-Nascimento et al. 2012; Bashandy et al. 2013; Cui et al. 2014) and trauma patients (Bakalar et al. 2006; Dechelotte et al. 2006; Grau et al. 2011). A recent review of glutamine supplementation trials in intensive care patients supports the view that it benefits patients by reducing length of hospital stay and rate of infectious complications (Coeffier and Dechelotte 2005).
In contrast, a pilot study of multiple trauma patients in intensive care given growth hormone plus alanyl-glutamine (AG) or AG supplements alone did not clearly show an attenuation of insulin resistance (inferred from glucose disposal rate) or incidence of hyperglycemia after enteral and parenteral nutrition in the AG group. Differences in timing of measurements and AG administration, dose, weight, and age of subjects were noted as possible reasons for this apparent reduced effect (Duska et al. 2008). Interestingly, this study used AG in combination with growth hormone for ethical reasons due to a previous report of increased mortality among patients receiving growth hormone treatment, with hyperglycemia and sepsis being more frequently reported in the growth hormone group. It was anticipated that glutamine would counter these adverse effects.
