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Type 1 diabetes is caused by insufficient insulin production.

Unlike in muscle and adipose tissue (GLUT4), glucose uptake by the liver is by GLUT2 and thus insulin-independent. Consequently, under very high blood glucose concentrations, glucose will move by facilitated diffusion into the liver.

However, insulin is not available to stimulate glycogenesis, or lipogenesis; glucagon will be secreted due to high blood glucose concentration, doing the opposite. What happens to this glucose? Does it simply diffuse back out (GLUT2 is bidirectional)? Presumably glucokinase produces glucose-6-phosphate, but the highly controlled points of glycolysis (e.g. PFK-1) will lack stimulation due to loss of insulin. Does a lack of glucagon (due to glucose still reaching pancreatic islet cells, also via GLUT2) have a positive effect?

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  • $\begingroup$ It would seem to me that as GLUT2 is not insulin-dependent, the net transport of glucose by it depends only on the difference between intracellular and blood glucose concentrations. I assume the liver has a high intracellular glucose concentration in diabetes because it is performing gluconeogenesis. Your question would then boil down to why is it doing this latter as the "starvation hormone", glucagon, is not secreted from the pancreas in diabetes (something I did not know, but checks out). Would this interpretation be correct? $\endgroup$ – David Nov 28 '19 at 13:56
  • $\begingroup$ That's true, presumably the net flow of glucose in type 1 diabetes in the liver is still outwards, due to excessive gluconeogenesis. I read that glucagon is still secreted by the alpha cells of the pancreas in type 1 diabetes (though the alpha cell mechanism is generally unclear; this might be due to paracrine signalling between beta and alpha cells; or some influence of the brain). In which case this would stimulate gluconeogenesis. Perhaps the lack of inhibition of gluconeogenesis (no insulin) is enough to tip regulation towards it rather than glycolysis (via F-1,6-BPase stimulation?). $\endgroup$ – pincushion44 Nov 28 '19 at 14:38
  • $\begingroup$ Seems reasonable. I should know the details of the regulatory control of the key points in the pathways, but only taught metabolism from the standpoint of feeding and fasting. If I had time (I'm away for a long weekend) I'd check it out in detail, but it appers that others may be saving me the task. $\endgroup$ – David Nov 28 '19 at 14:45
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1) Hepatic glucose intake may not be much greater in hyerglycemia than in normoglycemia:

Regulation of Hepatic Glucose Uptake and Storage In Vivo (Advances in Nutrition, 2012):

...neither hyperinsulinemia nor hyperglycemia can independently induce much net hepatic glucose uptake.

2) Glucose can be used for de novo lipogenesis in the liver despite the lack of insulin:

De Novo Lipogenesis and Cholesterol Synthesis in Humans with Long-Standing Type 1 Diabetes Are Comparable to Non-Diabetic Individuals (PLoS One, 2013):

Fasting total hepatic lipogenesis (3.91±0.90% vs. 5.30±1.22%; P = 0.41) was not significantly different between diabetic and control groups...

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