Some Thoughts on Metformin (reposted from 2016-08-09)

I think there’s some useful insight into one Oral Diabetes medication in the following originally from Aug 8, 2016.

From Wikipedia, here’s why Metformin is a good drug for dealing with Insulin Resistance and, for me, worked well for years.

Gluconeogenesis is also a target of therapy for type 2 diabetes, such as the antidiabetic drug, metformin, which inhibits glucose formation and stimulates glucose uptake by cells.

The phrase “stimulates glucose uptake by cells” is equivalent to “helps lower insulin resistance”. From this NIH paper (2000), you can see why Metformin works and how it doesn’t quite work well enough in a diabetic person.

The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 ± 0.05 vs. 0.36 ± 0.03 mmol · m−2 · min−1, P < 0.0001). Metformin reduced that rate by 24% (to 0.53 ± 0.03 mmol · m−2 · min−1, P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 ± 0.9 mmol/l, P = 0.0002).

So diabetics produced 2x the insulin of non-diabetics (100%) but Metformin only reduced that rate by 24%. Better than nothing but not nearly enough to make the diabetic person “normal”. And insulin resistance is a progressive disease by which the cells get better and better at not unlocking for insulin.

Going on in the paper.

The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 ± 0.03 vs. 0.18 ± 0.03 mmol · m−2 · min−1) and metformin reduced that rate by 36% (to 0.38 ± 0.03 mmol · m−2 · min−1, P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 ± 0.04 mmol · m−2 · min−1), which decreased by 33% after metformin treatment (0.28 ± 0.03 mmol · m−2 · min−1, P = 0.0002).

It keeps getting better. A diabetic person is 3x better at gluconeogenesis but Metformin ws only able to reduce that so that the diabetic person was at 2x the normal person.

And note, Metformin is about as good as it gets in that category of drug. Looks like it can help, but not solve the issues with gluconeogenesis. Something is better than nothing but don’t get lulled (like I was) into assuming all is well. If we keep filling up those protein stores than the same problem which happened to us with carbs will also happen to us with proteins.

Fatty Liver and Metformin

A randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease (Scand J Gastroenterol. 2009;44(7):853-60. Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial. Haukeland JW1, Konopski Z, Eggesbø HB, von Volkmann HL, Raschpichler G, Bjøro K, Haaland T, Løberg EM, Birkeland K.).

Forty-eight patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD) were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months.

The study concluded that:

Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD.

Could it be because the liver is already full and can’t get fatter?

[Afterthoughts]

I still thought it was protein in the diet that was the problem with GNG. There’s some dispute in the literature about whether GNG is affected by the fat in the liver or not (Nutrients. 2013 May; 5(5): 1544–1560. Non-Alcoholic Fatty Liver Disease (NAFLD) and Its Connection with Insulin Resistance, Dyslipidemia, Atherosclerosis and Coronary Heart Disease Melania Gaggini, Mariangela Morelli, Emma Buzzigoli, Ralph A. DeFronzo, Elisabetta Bugianesi, and Amalia Gastaldelli).

It looks like the final word may be in this study (Gastroenterology. 2007 Aug;133(2):496-506. Epub 2007 May 1. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastaldelli A1, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, Buzzigoli E, Sironi AM, Cersosimo E, Ferrannini E, Defronzo RA.). The study found that fat in the liver wasn’t the source of GNG, but visceral fat tissue.

Excess VAT primarily increases GNG flux.

Protein doesn’t turn to chocolate cake. Your Dawn Syndrome isn’t from the chicken you had last night. It’s from the cookies you ate three years ago.

Gluconeogenesis – Later Thoughts

I’ve spend time thinking about Gluconeogenesis (GNG). That’s the process where the liver creates glucose from other substrates, including Protein. Earlier on I though Protein was the culprit and was limiting my Protein intake. I don’t believe that was the problem. I believe that the problem was that my liver was overproducing glucose because it was overly fat.

And it turns out that the liver of a diabetic is particularly good at gluconeogensis. From this paper (Diabetes. 2000 Dec; 49(12): 2063–2069. Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes. Ripudaman S. Hundal, Martin Krssak, Sylvie Dufour, Didier Laurent, Vincent Lebon, Visvanathan Chandramouli, Silvio E. Inzucchi, William C. Schumann, Kitt F. Petersen, Bernard R. Landau, and Gerald I. Shulman) GNG is shown to be around 2x as good as a non-diabetic.

The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 ± 0.05 vs. 0.36 ± 0.03 mmol · m−2 · min−1, P < 0.0001).

And later in the paper:

The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 ± 0.03 vs. 0.18 ± 0.03 mmol · m−2 · min−1)

 

 

TED Talks on Diabetes/Diet (republished from 2016-08-09)

Want to spend a very confusing day? Watch a bunch of TED talks on the T2D subject by different speakers.

Here’s a sampling:

  1. Vegetarian guy who says meat is the problem with everything that ails us. His buddy the vegan weightlifter. Another vegetarian guy. They tell me I am not getting enough starch. They have not got the slightest clue about insulin resistance. My conclusion is they own stock in casket manufacturers.
  2. Paleolithic diet critic who is an archaeologist who points out the holes in the Paleo diet. Seems like the truth is we no longer have the ancient grasses food nor range fed animals so we are pretty much screwed either way.
  3. Food pyramid critics who say all those carbs aren’t all that good for us. (All of them fall into this category).
  4. Fat has been good for us all the way along woman. She is right. The belief that fat makes us fat is flawed and disproven.
  5. Guy who says everything we can possibly eat is poison.
  6. Sugar is the problem guy.
  7. Throw out the food pyramid woman. Fits in with Low Carb advocates.

They all have some unique insights. They all have some overlapping points.

The last one is the best (IMO) of all of the talks.

Her key points are:

  1. Carbs are making us sick.
  2. We don’t need carbs.
  3. Cutting carbs helps T2Ds by lowering their insulin.
  4. 40%+ of heart attacks are caused by insulin resistance.
  5. Lowering carbs lowers insulin requirements.
  6. Diabetes is reversible via low carb diet.
  7. Protein and carbohydrates all create glucose.
  8. Fat is what remains and it is good.

Practically this means eating food from the outside ring of the supermarket. Nothing out of the middle rows. No pasta, no cereal, nothing made of wheat, none of the processed foods in the middle. Outside ring is vegetables, meat, dairy, eggs. Maybe 15% of the stuff in the store.

 

Studies on Fasting

Studies on Fasting will be listed here.

Diabetes Studies

Here are Studies specifically on the effects of diets on Diabetes (particularly low carbohydrate diets).

These are studies related to diabetes in general:

 

Protein-Sparing Modified Fast (PSMF) Weight Loss Studies

Here are some of the scientific studies concerning Protein Sparing Modified Fasts (PSMF) and high protein diets.

PSMF Diets

Muscle Protein Synthesis

Studies on Protein and Diabetes

Protein as a Macronutrient and Protein Requirements

Very Low Carbohydrate Studies

This BLOG post will list Low Carbohydrate Diet Studies and will grow with time. New studies will be added to the end of this list.