Insulin suppresses and counterregulatory hormones increase proteolysis. Therefore, if proteolysis were a major factor determining amino acid fluxes in plasma, one would expect release of glutamine into plasma to be suppressed by insulin under euglycemic conditions and to be stimulated under hypoglycemic conditions. However, release of glutamine into plasma remains unaltered or increases during euglycemic hyperinsulinemia and decreases during insulin-induced hypoglycemia. To investigate the mechanisms for these paradoxical observations and the role of skeletal muscle, we infused overnight fasted volunteers with [U-14C] glutamine and measured release of glutamine into plasma, its removal from plasma, and forearm glutamine net balance, fractional extraction, uptake and release during 4-hour euglycemic (--5.0 mmol/L, n = 7) and hypoglycemic (∼3.1 mmol/L, n = 8) hyperinsulinemic (∼230 pmol/L) clamp experiments. During the euglycemic clamps, plasma glutamine uptake and release (both P <.05) and forearm muscle glutamine fractional extraction(P <.05), uptake (P < .02) and release (P <.01) all increased, whereas forearm glutamine net balance remained unchanged. The increase in muscle glutamine release (from 1.85 ± 0.26 to 2.18 ± 0.30 μmol . kg-1 . min-1) accounted for approximately 60% of the increase in total glutamine release into plasma (from 5.54 ± 0.47 to 6.10 ± 0.64 μmol . kg-1 . min-1) and correlated positively with the increase in muscle glucose uptake (r = 0.80, P <.03). During the hypoglycemic clamps, plasma glutamine uptake and release and forearm glutamine release remained unaltered, but forearm glutamine fractional extraction and uptake decreased approximately 25% (both P <.01) so that forearm glutamine net release increased from 0.37 ± 0.06 to 0.61 ± 0.09 μmol . kg-1. min-1 (P <.03). We conclude that skeletal muscle is largely responsible for the increased release of glutamine into plasma during euglycemic hyperinsulinemia in humans, and that this may be due to increased conversion of glucose to glutamine as part of the glucose-glutamine cycle; during hypoglycemic hyperinsulinemia decreased glutamine uptake by skeletal muscle may be important for providing substrate for increased glutamine gluconeogenesis.
I see cells dumping glutamine when insulin forces them to switch over to glucose metabolism. What do you see?
Aims/hypothesis Diet-induced obesity (DIO) is associated with insulin resistance in liver and muscle, but not in adipose tissue. Mice with fat-specific disruption of the gene encoding the insulin receptor are protected against DIO and glucose intolerance. In cell culture, glutamine induces insulin resistance in adipocytes, but has no effect in muscle cells. We investigated whether supplementation of a high-fat diet with glutamine induces insulin resistance in adipose tissue in the rat, improving insulin sensitivity in the whole animal.
Materials and methods
Male Wistar rats received standard rodent chow or a high-fat diet (HF) or an HF supplemented with alanine or glutamine (HFGln) for 2 months. Light microscopy and morphometry, oxygen consumption, hyperinsulinaemic-euglycaemic clamp and immunoprecipitation/ immunoblotting were performed. Results HFGln rats showed reductions in adipose mass and adipocyte size, a decrease in the activity of the insulin-induced IRS-phosphatidylinositol 3-kinase (PI3-K)-protein kinase B-forkhead transcription factor box 01 pathway in adipose tissue, and an increase in adiponectin levels. These results were associated with increases in insulin-stimulated glucose uptake in skeletal muscle and insulin-induced suppression of hepatic glucose output, and were accompanied by an increase in the activity of the insulin-induced IRS-PI3-K-Akt pathway in these tissues. In parallel, there were decreases in TNFα and IL-6 levels and reductions in c-jun N-terminal kinase (JNK), IκB kinase subunit β (IKKβ) and mammalian target of rapamycin (mTOR) activity in the liver, muscle
and adipose tissue. There was also an increase in oxygen consumption and a decrease in the respiratory exchange rate in HFGln rats.
Conclusions/interpretation Glutamine supplementation induces insulin resistance in adipose tissue, and this is accompanied by an increase in the activity of the hexosamine pathway. It also reduces adipose mass, consequently attenuating insulin resistance and activation of JNK and IKKβ, while improving insulin signalling in liver and muscle.
Glutamine increases muscle insulin sensitivity by inducing fat insulin resistance? I think tumour necrosis factor alpha and Il-6 levels in this case are probably signs that the animals are better maintained.
Reduced RQ and an increase in oxygen use-- that usually means more fat used for energy. The rats fat (and bone) probably puts out less leptin, making the muscles less biased towards fat oxidation and more open to the possibilities of glucose. Less leptin plus less insulin in the muscle cells might mean less metabolic over-steering.
An interesting note. The insulin in the first study made muscles put out glutamine. Do they put out enough glutamine to cause insulin resistance in the fat cells, which would make the muscle cells more insulin sensitive? Is this a significant part of the regulation of body fat?
WAIT A MINUTE. It sort of sounds like the muscles are trying to reduce the glucose in the system, like this is a vote for glutamine and or fat metabolism. Insulin sensitivity in muscles means making glutamine, rather than burning glucose?
This reminds me of those "Can you imagine a world without sand" type movies back in, well, not back in my school days. But you know, back in the school days they show in sitcoms. Glutamate, glutamine. The most dirt-common proteins in the body. So of course they're crucial, I guess.
Is metabolic syndrome a blood glutamine deficiency? At least, a functional one? I did pose it as a question this time, so if it's off to the funny farm, at least this post probably won't be the cause.