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

The catabolic state

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)

  • 114 ICU patients admitted for: multiple trauma
  • (38)

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.

 
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