Metformin action and insulin resistance

[PerSpinasAdAstra]

Moderator Note: This side discussion was split away from an earlier thread https://forum.diabetes.org.uk/board...void-metformin-im-trying.110227/#post-1321590

Will metformin lower my average and my spikes? Spikes are going up to 11 or 12. I also didn't know you can start metformin then come off....

Metformin works primarily by inhibiting glucose secretion into the bloodstream from the liver. The liver usually secretes glucose when it 'detects' that levels of insulin in the bloodstream are low. The insulin in the blood is secreted by the pancreas when it 'detects' that there is lots of glucose in the blood, such as immediately after eating carbohydrates. As such, the liver should only secrete much glucose when a person hasn't eaten for a while. This system, in a healthy person, ensures that the body has a constant, sufficient supply of glucose when you're not eating, such as when you're asleep. In a typical Type 2 diabetic however the liver is thought to be 'insulin resistant' - i.e. it is no longer able to respond to blood insulin levels properly. As a result it pumps out glucose much more than it would in a healthy person. Metformin puts the brakes on glucose output from the liver, and as a result should bring down baseline blood glucose levels a bit throughout the day. It is also thought to enable insulin to work a little more effectively in some way, though I have not learned how that works yet.

Metformin is typically the first medication prescribed for Type 2 because it is regarded as a safe medication that is generally well tolerated. While a considerable number of people experience some side effects in the beginning, the great majority of people tolerate the medication very well after their bodies get used to it. There are some serious potential side effects to be aware of, so always read the patient information leaflet if you are prescribed it, but those occur rarely. In my case I chose to go on metformin, and while I hope to be able to go off it some day I'm content to take it for the rest of my life, if necessary, to preserve my health. I did experience some side effects, particularly a little nausea after taking it, but after a month or so I had zero side effects that I could sense.

As with almost all medications your doctor will deprescribe it, take you off it, if you no longer need it. You should always talk to your doctor and discuss it before going off any medication.

Best of luck

 

[harbottle]

Metformin works primarily by inhibiting glucose secretion into the bloodstream from the liver. The liver usually secretes glucose when it 'detects' that levels of insulin in the bloodstream are low. The insulin in the blood is secreted by the pancreas when it 'detects' that there is lots of glucose in the blood, such as immediately after eating carbohydrates. As such, the liver should only secrete much glucose when a person hasn't eaten for a while. This system, in a healthy person, ensures that the body has a constant, sufficient supply of glucose when you're not eating, such as when you're asleep. In a typical Type 2 diabetic however the liver is thought to be 'insulin resistant' - i.e. it is no longer able to respond to blood insulin levels properly. As a result it pumps out glucose much more than it would in a healthy person. Metformin puts the brakes on glucose output from the liver, and as a result should bring down baseline blood glucose levels a bit throughout the day. It is also thought to enable insulin to work a little more effectively in some way, though I have not learned how that works yet.

The liver produces glucose due to the release of Glucagon from the pancreas, which is released from alpha cells when blood sugar levels are low and also in response to some types of meals.

The liver really is just a slave to insulin and glucagon - insulin stops glycolysis or gluconeogenesis and also promotes the storage of glucose in the liver (A large chunk of glucose from a meal ends up on the liver as glycogen.) Glucagon promotes the release.

I don't think they know how Metformin improves insulin sensitivity in muscles.

 

[PerSpinasAdAstra]

The liver produces glucose due to the release of Glucagon from the pancreas, which is released from alpha cells when blood sugar levels are low and also in response to some types of meals.

The liver really is just a slave to insulin and glucagon - insulin stops glycolysis or gluconeogenesis and also promotes the storage of glucose in the liver (A large chunk of glucose from a meal ends up on the liver as glycogen.) Glucagon promotes the release.

I don't think they know how Metformin improves insulin sensitivity in muscles.

Thanks for this, I must have misunderstood something along the way. I thought I had read somewhere that 'insulin resistance' in the liver causes raised blood glucose levels, and I suppose I assumed that insulin resistance is what causes it to excrete more glucose than it should. So if I'm reading what you've said here correctly, insulin resistance in the liver actually prevents it from storing glucose in response to high insulin levels? And that is the mechanism linking liver insulin resistance and higher blood glucose levels?

EDIT - Trying to read this document but it's hard going for me. I don't understand the mechanism but I suppose I don't need to - fatty liver bad, make fat go away - that's all I need to know for now 😉

Molecular Pathophysiology of Hepatic Glucose Production

Maintaining blood glucose concentration within a relatively narrow range through periods of fasting or excess nutrient availability is essential to the survival of the organism. This is achieved through an intricate balance between glucose uptake and ...

www.ncbi.nlm.nih.gov

"In the diabetic state, the liver also becomes resistant to the actions of insulin and several studies have shown that hepatic glucose production is increased in patients with T2DM (Campbell et al., 1988; Consoli et al., 1989; DeFronzo et al., 1982; Magnusson et al., 1992). Several studies have also clearly demonstrated that the increase in HGP during fasting in the diabetic state is primarily the result of an increase in gluconeogenesis and that glycogenolysis remains unchanged (Magnusson et al., 1992). Therefore, in the diabetic state it is hepatic insulin resistance and the consequent increase in hepatic glucose production that is the major contributor to postabsorptive and postprandial hyperglycemia."

 

[harbottle]

No, you are right insulin resistance in the liver does cause runaway generation of glucose, but the mechanism to produce glucose isn't based on insulin levels being detected by the liver, but glucagon levels triggering glycolysis or gluconeogenesis. Insulin resistance means it doesn't stop when it's supposed to, although I've read some papers that hypothesise that the amount of raw materials (Fats and amino acids) keeps the process going.

 

[Burylancs]

Thanks for this, I must have misunderstood something along the way. I thought I had read somewhere that 'insulin resistance' in the liver causes raised blood glucose levels, and I suppose I assumed that insulin resistance is what causes it to excrete more glucose than it should. So if I'm reading what you've said here correctly, insulin resistance in the liver actually prevents it from storing glucose in response to high insulin levels? And that is the mechanism linking liver insulin resistance and higher blood glucose levels?

EDIT - Trying to read this document but it's hard going for me. I don't understand the mechanism but I suppose I don't need to - fatty liver bad, make fat go away - that's all I need to know for now 😉

Molecular Pathophysiology of Hepatic Glucose Production

Maintaining blood glucose concentration within a relatively narrow range through periods of fasting or excess nutrient availability is essential to the survival of the organism. This is achieved through an intricate balance between glucose uptake and ...

www.ncbi.nlm.nih.gov

"In the diabetic state, the liver also becomes resistant to the actions of insulin and several studies have shown that hepatic glucose production is increased in patients with T2DM (Campbell et al., 1988; Consoli et al., 1989; DeFronzo et al., 1982; Magnusson et al., 1992). Several studies have also clearly demonstrated that the increase in HGP during fasting in the diabetic state is primarily the result of an increase in gluconeogenesis and that glycogenolysis remains unchanged (Magnusson et al., 1992). Therefore, in the diabetic state it is hepatic insulin resistance and the consequent increase in hepatic glucose production that is the major contributor to postabsorptive and postprandial hyperglycemia."

Insulin Resistance in Type 2s is largely at the cell level. The cells are slathered in fat making the Insulin Receptor Ports and the Glucose Receptor Ports inaccessible. In addition between 20 and 30% of Type 2s have nonexistent or stubby tethers on their insulin which prevents the insulin tethering itself to the Insulin Receptor. No signal is sent and the GLUTs slumber on instead of swarming up to collect the glucose. GLUT4 has also been suggested as a culprit in IR - legging out through the hole in the cell wall with the glucose instead of taking it down to the nucleus of the cell.

Losing weight means IR is improved, the 1955 research quantified it as losing 10% of body weight improves control significantly, simply because with a much reduced demand for insulin the pancreas is better able to meet the demands made on it.

 

[PerSpinasAdAstra]

Insulin Resistance in Type 2s is largely at the cell level. The cells are slathered in fat making the Insulin Receptor Ports and the Glucose Receptor Ports inaccessible. In addition between 20 and 30% of Type 2s have nonexistent or stubby tethers on their insulin which prevents the insulin tethering itself to the Insulin Receptor. No signal is sent and the GLUTs slumber on instead of swarming up to collect the glucose. GLUT4 has also been suggested as a culprit in IR - legging out through the hole in the cell wall with the glucose instead of taking it down to the nucleus of the cell.

Losing weight means IR is improved, the 1955 research quantified it as losing 10% of body weight improves control significantly, simply because with a much reduced demand for insulin the pancreas is better able to meet the demands made on it.

Thanks for this. I won't post again on this thread on this topic as the original poster is likely bewildered at how far off topic this thread has gone 😉

I was aware that insulin resistance occurs at the cellular level and that fat plays a major role. I've been trying to learn more about it from the perspective of learning what, if anything, can be done to reverse it, looking at each type of cell individually. It's proving to be an extremely complex topic and all the good, freely available information is in the form of scientific papers, which I find very difficult and time consuming to read and understand. I tried looking for a good book on the subject but most of them are trash, and the one fairly recent book that looks promising 'Understanding Insulin and Insulin Resistance' by Anil Gupta costs $180 US and isn't even aimed at reversal, just explaining how it comes about.

Losing weight appears to help matters in a number of ways, as does regular exercise. However, once I've lost the weight, is there merit in trying to build muscle and then maintaining it, purely from the perspective of improving blood glucose control and insulin sensitivity? On the one hand building muscle and exercising it regularly will help to burn off ectopic fat stored in the muscle tissue, apparently improving insulin resistance in that muscle tissue. It will cause muscle tissue to soak up more glucose and fat after long periods of exercise as it replenishes glycogen and fat stores. However, does larger muscle mass also imply a larger whole-body demand for insulin? Is it better for the long term health of my pancreas to just lose the weight and exercise the muscle I have, or try to increase my muscle mass significantly and train to run 5K three times per week? That would be immensely challenging for me, but I'd consider doing it if it meant both better long term blood glucose control and better prospects for slowing the progression of my diabetes.

There's plenty of information about diet available, relatively speaking, but precious little about insulin resistance, the exact effects of weight loss, and exercise strategies. Figuring it out for myself is proving very difficult.

 

[Burylancs]

Thanks for this. I won't post again on this thread on this topic as the original poster is likely bewildered at how far off topic this thread has gone 😉

I was aware that insulin resistance occurs at the cellular level and that fat plays a major role. I've been trying to learn more about it from the perspective of learning what, if anything, can be done to reverse it, looking at each type of cell individually. It's proving to be an extremely complex topic and all the good, freely available information is in the form of scientific papers, which I find very difficult and time consuming to read and understand. I tried looking for a good book on the subject but most of them are trash, and the one fairly recent book that looks promising 'Understanding Insulin and Insulin Resistance' by Anil Gupta costs $180 US and isn't even aimed at reversal, just explaining how it comes about.

Losing weight appears to help matters in a number of ways, as does regular exercise. However, once I've lost the weight, is there merit in trying to build muscle and then maintaining it, purely from the perspective of improving blood glucose control and insulin sensitivity? On the one hand building muscle and exercising it regularly will help to burn off ectopic fat stored in the muscle tissue, apparently improving insulin resistance in that muscle tissue. It will cause muscle tissue to soak up more glucose and fat after long periods of exercise as it replenishes glycogen and fat stores. However, does larger muscle mass also imply a larger whole-body demand for insulin? Is it better for the long term health of my pancreas to just lose the weight and exercise the muscle I have, or try to increase my muscle mass significantly and train to run 5K three times per week? That would be immensely challenging for me, but I'd consider doing it if it meant both better long term blood glucose control and better prospects for slowing the progression of my diabetes.

There's plenty of information about diet available, relatively speaking, but precious little about insulin resistance, the exact effects of weight loss, and exercise strategies. Figuring it out for myself is proving very difficult.

Bernstein (a popular diabetes guru twenty/thirty years ago) was big on muscle building. He even had his little old lady patients pumping dumbbells. His point was that anaerobic exercise ( working weights until the muscles ached) drew large amounts of glucose immediately out of the system and built muscles that used more glucose anyway. Double Bubble.

 

[everydayupsanddowns]

Thanks for this. I won't post again on this thread on this topic as the original poster is likely bewildered at how far off topic this thread has gone 😉

No problem at all @PerSpinasAdAstra

I've split these posts away into a separate thread so that you can continue the conversation if you'd like to 🙂