Metformin and Weight Loss (From Aug 2016)

Metformin is said to do two paradoxical things at the same time:

  1. Metformin lowers insulin resistance which helps glucose to be moved from the bloodstream to the cells (The science: Reducing insulin resistance with metformin: the evidence today).
  2. Metformin used alone results in some weight loss (The science: 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study).

Here’s the paradox. If insulin is only used for pushing fat into cells then Metformin, by lowering insulin resistance should increase weight, right? What am we missing here?

One obvious answer is that insulin is the key to both pushing fat into cells as well as releasing fat from cells. Lowering insulin resistance helps take the fat from the cells and explains Metformin’s advantages. Metformin is like a key which opens the lock and allows glucose in and out of cells.

I know from my own experience that even after 5 years on the pump Metformin still helps my blood sugar levels – by roughly 20 points when taken at bedtime. Instead of waking up at 140 I wake up at 120 by taking Metformin before bed.

Metformin lowers insulin resistance. Lowering our insulin resistance both helps us take up the glucose from our blood into our cells and helps us lose weight.

Take note, I am not saying any of this to advocate for Metformin. The same study showed that Metformin can delay the onset of diabetes by as much as 10 years if given to pre-diabetics. But it is still only a delay.

Who Would Have Thought? (Repost from Aug 2016)

Who would have thought that lowering insulin use while keeping blood glucose levels stable was even possible? I don’t remember hearing that in my pump training class. They talked about how to increase insulin not decrease insulin.

Who would have thought that it would be this easy to better regulate their blood sugar levels? Skipping breakfast and lunch sounds too simple.

Why does this work?

We fast every day. If we ate our last meal or snack at 8 PM and eat breakfast the next day at 8 AM we’ve just done a 12 hour fast. But for insulin resistant people the Dawn Syndrome robs us of the advantage of that fast. We wake up and our numbers are higher than they should be. Increasing our pump basal amounts doesn’t help either. (In fact, if this model is right it makes it even worse).

How is extending the fast by 4-8 hours beneficial? Well, instead of stepping up from our early number (as breakfast does) we keep steadily going down in blood sugar levels. Dr Feng’s view is that there’s a transition from using stored energy in the liver to stored energy in the body’s fat cells themselves. That transition is how we lose weight and affect the insulin resistance.

A few drugs, like Metformin, can help, but not enough over a long time, We’ve got to extend our reset period and the best way to do that is through fasting.

The Shift in Thinking

The main shift in thinking was going from believing that insulin is a neutral substance which only helps to lower blood sugar. If insulin itself is the problem then treating with insulin is throwing fuel on that same fire. No wonder we keep getting sicker and sicker.

Insulin is a hormone

From this site.

Insulin is a hormone made by the pancreas that allows your body to use sugar (glucose) from carbohydrates in the food that you eat for energy or to store glucose for future use.

The same site says this.

People with type 2 diabetes do not respond well or are resistant to insulin. They may need insulin shots to help them better process sugar and to prevent long-term complications from this disease. Persons with type 2 diabetes may first be treated with oral medications, along with diet and exercise. Since type 2 diabetes is a progressive condition, the longer someone has it, the more likely they will require insulin to maintain blood sugar levels.

So let’s try and follow the conventional wisdom.

  • T2Ds don’t handle insulin well (insulin resistance)
  • T2Ds need shots to get more insulin
  • Eventually oral meds will need to be replaced with insulin in T2Ds.

That’s the best they have to offer on these sites. The problem isn’t blood sugar levels it’s our response to insulin. No real insight is given on how to improve insulin resistance. No comment on the underlying problem at all.

 

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 (How Metformin Works) 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 paper (Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49(12):2063-9), 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 was 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)

 

 

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.