All about Insulin and insulin resistance at an advanced level

A friend of mine was listening to this podcast and thought I might be interested. As many of you regulars know, I’m not much of a techie, but I thought some of you might appreciate this so I’m attaching it so that you know about it. I personally have not listened to the podcast and probably will not.

Gerald Shulman is a Professor of Medicine, Cellular & Molecular Physiology, and the Director of the Diabetes Research Center at Yale. His pioneering work on the use of advanced technologies to analyze metabolic flux within cells has greatly contributed to the understanding of insulin resistance and type 2 diabetes. In this episode, Gerald clarifies what insulin resistance means as it relates to the muscle and the liver, and the evolutionary reason for its existence. He goes into depth on mechanisms that lead to and resolve insulin resistance, like the role of diet, exercise, and pharmacological agents. As a bonus, Gerald concludes with insights into Metformin’s mechanism of action and its suitability as a longevity agent.
We discuss:
• Gerald’s background and interest in metabolism and insulin resistance (2:30);
• Insulin resistance as a root cause of chronic disease (6:30);
• How Gerald uses NMR to see inside cells (10:00);
• Defining and diagnosing insulin resistance and type 2 diabetes (17:15);
• The role of lipids in insulin resistance (29:15);
• Confirmation of glucose transport as the root problem in lipid-induced insulin resistance (38:15);
• The role of exercise in protecting against insulin resistance and fatty liver (48:00);
• Insulin resistance in the liver (1:05:00);
• The evolutionary explanation for insulin resistance—an important tool for surviving starvation (1:15:15);
• The critical role of gluconeogenesis, and how it’s regulated by insulin (1:20:30);
• Inflammation and body fat as contributing factors to insulin resistance (1:30:15);
• Treatment approaches for fatty liver and insulin resistance, and an exciting new pharmacological approach (1:39:15);
• Metformin’s mechanism of action and its suitability as a longevity agent (1:56:15); and
• More.


I can’t wait until I get to this part. This is the first I have seen that verifies my opinion that insulin resistance is an evolutionary mechanism to stave of famine. It allows enough individuals to have offspring. My hypothesis is the mechanism is triggered by chemical and enzymic changes in food as it ages.

BTW this would be good for both type 1 and 2 diabetics to listen. The proportion of people with insulin resistance that are type 1 is probably equal to the general population.


Thanks for the link. I can’t wait to read it.

It’s an audio pod cast

Thanks for the link @bostrav59 ! This is going to be my TDay diversion :microscope:

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Dr. Bernstein’s book “the Diabetes Solution” has been saying this about T2Ds since 1997! He just never investigated it, focused instead on improving patients’ - and his own - lives.

For just as long, Dr B has advocated the use of metformin (originally from the French lilac) for T2D AND T1Ds. I for one, also take metformin.

Thanks for sharing!

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Whoa - this was a long time ago so I had to go back to the post and see what I was talking about.

When you were quoting me, that was the synopsis from the podcast. I still haven’t listened to it. Has anyone done so? Would anyone recommend it?

Thanks @CarlosLuis - I appreciate your theory about evolution and insulin but I don’t know enough about it to have an opinion.


I will listen to this Monday as I have stuff to do this weekend. I have long thought that insulin resistance and the reduction of energy with fat storage that can result in developing type 2 DM is a famine survival tool. We see this in livestock, some are easy keepers, tending to fat on lower rations while others are hay burners (think race horses) who have to eat constantly or lose condition.

My untested hypothesis as to why T2DM is increasing in populations that are not experiencing famine, such as in developed nations, is possibly the result of chemical changes in our food supply that mimics those of food in times of famine. Much of our food is process, preserved and not particularly fresh. This is similar to the food that is available during annual starving times in hunter gatherers. Starving time begins in winter, continues through spring and can continue into early summer. It ends when fresh foods become available naturally and people are depending upon stored and preserved foods.

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I agree with this. We humans are mammals afterall. We are effected by food sources just like other creatures but being at the top of the food chain we seem to forget what food is healthy for us.


@MsCris can you share more about your metformin regimen? I talked w my new endo about GLP-1 and she was more amenable to metformin, but I want to understand the why better, if you have the time. Thanks!


Hi @JessicaD I’m T1 and also take metformin 1000mg 1x/d. I started on it when I was slowly inching towards the diabetic A1C threshold and wasn’t yet eligible for insulin. Although I didn’t see any improvement to my A1C from it I’ve continued using it because it may be providing some benefits in terms of insulin sensitivity, and because I don’t have any adverse GI reactions. However, I need to supplement with B12 to make sure I don’t become deficient (a known effect of long term metformin use). I would certainly be open to dropping the metformin since I hate taking more meds than I (may) need.


It would be a good idea to go through the action of the medication, just to get an idea of what is actually “does”.

Metformin decreases the amount of glucose your liver produces and releases. It can slow your digestion. And it may possibly (see footnote below)* increase the secretion of GLP-1.

What does that do? GLP-1 inhibits glucagon release. And less glucagon means lower BG.

So less glucagon and less glucose from you liver. Simple so far…

While that’s all well-and-good for someone with T2 who still has somewhat functioning alpha cells (glucagon), if your alpha cells are no longer doing anything, then metformin won’t have the effect of reducing glucagon. So it may not be as useful for you as it is for a T2. It just depends on if your body still has a glucagon response.

But for a T1, metformin can still do things that help. It can reduce the amount of glucose your liver produces. It can slow down how quickly you digest food, which reduces BG spikes after a meal. Things like that, etc.

So those things might be good for you, it just depends if that is what you want. Like when is your BG high, etc.

(I personally think slowing down how quickly my food digests would be less desirable for me. Like if you eat and it takes you longer to digest, that means you would need to keep an eye on your BG for a longer time! But for others, reducing spikes right after eating a meal might help. It just depends on the person and how they interact with their meals and insulin and their CGM and BG testing and all of that. And as far as reducing the amount of glucose my liver can release - I do everything I can to INCREASE that! For me, it’s a valuable fuel source.)

So I think it would be really helpful to understand all of the things these medications actually do, and see if those are things would be helpful for you and see if it is something you would want.

Above I said, "
…it may possibly increase the secretion of GLP-1.*"

Why did I say “possibly”? Because they don’t actually know! The increase in GLP-1 may just be a side-effect of the reduction in the liver’s glucose production. Like they don’t even know if metformin interacts directly with GLP-1 or if that is just the body’s response to other things metformin is doing.

Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown.

The mechanisms underlying these benefits are complex and still not fully understood.

Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown.


@JessicaD I take 500mg extended release , 2x/day.

It’s been a few years, but I recall I had some nausea when I started, took a few weeks to calm down, then none at all. (While some experience diarrhea, I did not.)

For me it helps a lot for dawn phenomenon and reduces how much insulin I need for protein - but only slightly for carbs. My insulin action was shorter, I now wait 30 min vs the 40min before metformin. My basal rate went down a tad at the time, too.

It is definitely worth it for me - seems to make my insulin more efficient, effective - and calms my liver down a bit. (Nothing like a GLP1/GIP, but still noticeable.) Overall, my management improved.

Takes a few months for full effect, so patience is key. As with all the therapies out there, right?


@jessicad, I’ve had a different experience on metformin. Like many of us older T1D’s, I was initially diagnosed as T2 and put on metformin as well as insulin. When I was correctly diagnosed (about 12 months later), the docs took me off metformin.

I didn’t notice any difference and was glad to have one fewer scrip, since I have so many in any event.


I read this article a few months ago and found it interesting.


Thank you all so much for your thoughts. Although I don’t love the idea of adding another medication to the mix, I see some significant potential benefits for me in metformin, particularly in reading the article that @Josie posted. (I also recognize and appreciate the downsides in @Eric’s post!) My dawn phenomenon/FOTF (actually both!) issue is huge and although I know starting an insulin pump could put that issue to bed, I just still cannot get my mind there (yes, this is enormously frustrating to me, but I’m trying to also be kind to myself?!). The slowing of digestion is definitely a potential downside and one that I would have to see how it manifested in my body. I think I am going to connect with my new endo and talk about this some more. Thank you again! Jessica


I want you to be armed with as much information as you can possibly get, because sometimes meetings with doctors turn into a bunch of medical jargon talk from them and it can be hard to follow.

Words they use like glycogenesis, gluconeogenesis, and glycogenolysis. Can they possibly come up with words that are a little more similar to make it even more confusing?!? :exploding_head:

Please be kind to yourself!

Just as a reference, I was dead-set against a pump for a while too. I went 43 years without a pump! The tubeless option and the ability to turn basal completely OFF were the things that changed my mind.

But all these things are completely personal choices and no two people have the same situation. So finding a way to do it best for your life is what you need to do.

And 1 more thing, if I may…


I bet you there is something you have not tried yet that can help this. And it actually does not require a prescription.

NPH has a really unique release curve. If you take a very small amount right before you go to bed, that would at least give your body a little bit of extra basal at the time when you are seeing your BG rise.

I know people will tell you horror stories about NPH, but that’s because they were using it as their only basal insulin, like back in the 50’s-80’s. They are talking about how they took a bunch of it in the morning and their BG dropped later in the day. And that was their only basal because nothing else existed. (That’s what I used too, way back!)

But this is a totally different use-case I am describing!

I actually kept using it in the way I described at night before bed after I switched over to Lantus. Because Lantus did not give me the increase I needed at 4am, but a few units of NPH taken around 11pm or whenever I went to bed worked much better with the Lantus.

It made sense. I need a little more insulin at 4-5am. NPH will come in around then and be a little extra on top of the Lantus.

So just another option to consider. You can get it for around $30 at any Walmart pharmacy with NO prescription!

It’s easy to try. You start with maybe 1/2 unit before bed. That won’t do much. But if you do that a few nights, at least you are not as nervous as you were before. Then bump it up to 1 unit, and see if it makes a difference. Etc, etc.

Super easy to try out.

(I can send you 1/2 unit syringes if you don’t have any. :grinning: )

Here is a little illustration. (glargine=Lantus). If the NPH level looks too scary for you because it is too high, that’s just because the illustration was done by this medical resource showing it with a comparable amount to the Lantus.

But in your case it would be much smaller because we are talking 1/2 unit or 1 unit or something like that, not an equal amount to the Lantus you are taking!

Check it out. How does that little peak around 5-6 hours look in your life, if you take it at 10-11pm? That lands right around 4am-ish for you.

Boom! A little less dawn phenomenon/FOTF. Maybe it does not completely remove it, but it certainly helps.


One other thing to add about the NPH stuff. :arrow_up:

Just so you know that this is not some fly-by-night idea, I STILL use this option on occasion, even owning a pump.

Like if my pod dies or expires right before I go to bed, and I don’t feel like putting a pod on super late before bed. I will take some Levemir AND NPH before bed. And then fix my pod in the morning.

And that option works so much better than just the Levemir by itself. :man_shrugging:


So metformin slows down digestion. Does anyone know how much it slows it down? Is it lot like a ozempic? Or would it just return type 1s to a more normal digestion since we tend to digest food faster than the average person?

I’m sure you already have done so but if you haven’t maybe get a prescription from your provider for a glucagon. Then maybe it can put your mind a bit at ease if digestion timing is too slow.

I’d actually be really interested in hearing your results after a couple of months! It’s something I’ve been thinking about for awhile. I’m ok with my weight but I have been abnormally hungry since I was diagnosed. I thought metformin might help with that.

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@Josie metformin won’t slow your digestion as much as Ozempic or Mounjaro. (Personal experience on all 3)