#40 Metformin For Patients With Type 1 Diabetes & May 2017 Update on My T1D Management

I would expect that the majority of those with diabetes, including type 1 diabetes (T1DM), have at least heard of the medication, metformin. It is primarily used to lower blood glucose (BG) in those with type 2 diabetes (T2DM), but does so by addressing insulin resistance, the primary defect in T2DM. However in recent years, it has been used “off-label” for persons with insulin resistance that leads to other conditions including pre-diabetes, severe obesity, polycystic ovarian syndrome (PCOS), cancer, and T1DM.

Its use in T1DM has been targeted to those with signs of insulin resistance which include hypertension, elevated serum triglycerides (>150 mg/dl), reduced HDL-C (<40 mg/dl in males or <50 mg/dl in females), overweight/obesity or elevated waist-to-height ratio (>0.5) (which includes about 25% of those with T1DM). Although any of these signs can be associated with insulin resistance, the more signs one has, the higher the risk of having insulin resistance. The term “double diabetes” has been used to describe those with T1DM who are also insulin resistant. Insulin resistance as has been reviewed in detail in my blog post #22 primarily in the context of prediabetes and type 2 diabetes. But you may ask, “How does a person with T1DM become insulin resistant?” You probably won’t hear very many provide an explanation for it, but here is mine. I think it is a combination of a diet high in refined (processed) carbohydrates and sugar with the use of exogenous insulin to cover those carbohydrates. Exogenous insulin is far from physiologic and there are many hours of the day or night where there is insufficient insulin to suppress hepatic (liver) glucose production leading to elevated BG (glucotoxicity): one of the proposed mechanisms of insulin resistance in T1DM. Additionally, there are hours of the day or night where insulin levels are excessive which can also contribute to insulin resistance. But most importantly the combination of taking lots of dietary carbohydrate, to which those with T1DM are intolerant, with lots of exogenous insulin, directly leads to insulin resistance just as it would in a person with prediabetes or T2DM (in their case the insulin would be endogenous in response to the dietary carbohydrate).

The use of metformin for cancer is still in the animal research arena primarily, but originates from the observation in population studies that patients with T2DM taking metformin was associated with reduced incidence and mortality rates of cancer compared to those not taking metformin.

As far as drugs go, metformin is particularly useful in addressing the problem of insulin resistance. Metformin improves insulin resistance by decreasing hepatic glucose production and intestinal glucose absorption and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. There have been numerous small studies of using metformin in patients with T1DM. A systematic review from 2010 found that “Metformin was associated with reductions in: (1) insulin-dose requirement (5.7–10.1 U/day in six of seven studies); (2) HbA1c (0.6–0.9% in four of seven studies); (3) weight (1.7–6.0 kg in three of six studies); and (4) total cholesterol (0.3–0.41 mmol/l in three of seven studies). Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia.” A meta-analysis of eight randomized-controlled trials published in 2015 came to similar conclusions: “Metformin was associated with a reduction in daily insulin dosage, body weight, total cholesterol level, low-density lipoprotein level, and high-density lipoprotein level but an increase in risk of gastrointestinal adverse effects compared with placebo treatment in T1DM patients. No significant difference was found between the metformin group and the placebo group in HbA1c level, fasting plasma glucose level, or triglycerides level. No significant difference was found between the metformin group and the placebo group in the risk of severe hypoglycemia or diabetic ketoacidosis.” Note: I had access only to the abstract so I can’t give you any more details from this meta-analysis.

I hope it goes without saying that insulin resistance is expressed in those with a genetic tendency who are also exposed to an adverse environment, in this case, dietary carbohydrate consumption, particularly refined (processed) carbohydrates and sugars, in excess of one’s tolerance. This may also require excess calorie consumption as well. However, there is good evidence to suggest that refined (processed) carbohydrates and sugars stimulate appetite and fat deposition (via the signal of increased insulin). Thus, there is a link between refined (processed) carbohydrate and sugar consumption and excess calorie consumption. It has also long been known that physical activity affects insulin resistance. Other things being equal, sedentary behavior increases the likelihood of insulin resistance whereas regular physical activity decreases it. Thus, the first-line treatment for insulin resistance should be carbohydrate restriction, shedding of excess body fat (if needed), and regular physical activity before initiating any drug therapy.

Personally, I have been contemplating trying metformin for my T1DM for many years, but have not done so because I have never had any signs of insulin resistance (see above). More recently however, I have decided to give it a try primarily for the purpose of seeing if metformin might further reduce my insulin requirement which could, in turn, further reduce the frequency of hypoglycemia. Since my insulin requirements do fluctuate significantly over time, I estimate that it could take many months (up to 6 months possibly) to understand whether or not metformin has reduced my insulin requirement. I might be surprised sooner if the effect is more dramatic than I anticipate of course. However, if I am already insulin sensitive, metformin may not improve it much further. So on June 1, I will start metformin at 250-500 mg twice daily with meals and possibly eventually increase to a maximum of 1,000 mg twice daily to see if there is any reduction in insulin doses or hypoglycemia. Needless to say, anyone contemplating a similar experiment with metformin should discuss that with their own physician.

Glycemic Management Results for May 2017

May 2017 glycemic results were rather typical despite travel and a back strain that eliminated exercise for 6 days this month. This also changed my exercise to a less insulin-sensitizing activity (walking instead of weightlifting) for several more days which in turn affects BG and insulin doses. My total daily insulin dose ranged from a high of 42 IU/day to a low of 24 IU/day. It still remains baffling how my insulin dose can vary so much in the span of one month. These changes in insulin doses are in response to both hypoglycemia (leading to a reduction in insulin doses) and hyperglycemia (leading to increases in insulin doses), but I had more hypoglycemia this month resulting in insulin dose reductions for most of the month. Fortunately, none of the hypoglycemic episodes were symptomatic. I also checked blood ketones twice this month, both values happened to be the same at 1.2 mM beta-hydroxybutyrate. I did not measure breath ketones this month.

Below are my mean blood glucose (BG) values, mean insulin doses, and BG frequency distribution for April 2017 compared to previous time periods.

Post 40 Means Table

As presented in blog post #15 exogenous insulin cannot mimic normal insulin secretion, so persons with type 1 diabetes (T1DM) should not expect to have truly normal BG values. They just need to be low enough to prevent long-term complications and not so low as to cause unpleasant hypoglycemic symptoms, brain damage, seizure, injury, coma, or death. I have set my target BG range at 61-110 mg/dl because values in this range are not likely to lead to harm or complications of T1DM. Your target BG range should be determined with your physician because one size does not fit all. Normal BG is 96 ± 12 mg/dl (mean ± standard deviation (SD)) and coefficient of variation is 13% which is the weighted mean from these two studies (here and here) of continuous glucose monitoring in healthy subjects. The standard deviation and coefficient of variation are measures of BG variability which I believe are important in T1DM. However, be advised that clinical outcomes in type 1 diabetes (i.e. microvascular and macrovascular complications) have only been documented to correlate with measures of mean BG, particularly HbA1c. This does not mean BG variability is not important, but it just has not been documented to correlate with outcomes and complications of T1DM. Achieving a normal standard deviation or coefficient of variation in T1DM would be difficult, if not impossible, with current exogenous insulin therapy (injected or pumped). I hope that adding a continuous glucose monitor (CGM) to my therapeutic regimen will improve my BG variability and thus the standard deviation and coefficient of variation. I plan to get the FreeStyle Libre CGM as soon as it becomes available in the U.S. Monitoring the standard deviation and/or coefficient of variation and finding ways to improve them to the best of one’s ability is desirable in my opinion. Following a low carbohydrate ketogenic diet is one such method of reducing BG variability, mean BG, insulin doses, and hypoglycemia. A ketogenic diet may also provide an alternate/additional brain fuel in the form of ketones to protect the brain when BG does go low. The alternative energy that ketones supply to the brain may prevent or blunt the sympathoadrenal response to hypoglycemia which in turn reduces or eliminates the symptoms of and harm from hypoglycemia. This hypothesis needs to be tested before it can be stated as fact. Having BG close to normal most of the time (some of which are hypoglycemic) also minimizes the symptoms of mild hypoglycemia and potentially the harm from hypoglycemia as well due to lack of activation of the sympathetic nervous system and adrenal gland responses to hypoglycemia i.e. sympathoadrenal-induced fatal cardiac arrhythmia, see here.

Below are my BG readings along with exercise type and time for May 2017.

Post 40 Blood Glucose and Exercise Graph

The table below shows the BG variability results for current and previous time periods. The percentiles (10th, 25th, 75th, 90th) on the right show the spread of the BG readings about the median. The interquartile range, the difference between the 75th and 25th percentiles, is a measure of BG variability. In the middle of the table are the %Time in three BG ranges: %Time BG < 61 mg/dl and the mean BG during that time, then %Time BG 61-110 mg/dl and the mean BG during that time, and %Time BG > 110 mg/dl and the mean BG during that time. The other measures of BG variability were defined and explained in blog post #10.

Post 40 Variability Table

The actual daily insulin doses and daily insulin dose totals are shown in the graphs below. I had to take multiple extra rapid-acting insulin doses to correct hyperglycemia and the breakfast and dinner rapid-acting insulin doses increased during the first week of the month. Then BG began decreasing with more hypoglycemia require progress reductions in rapid-acting insulin doses. I made small changes in my basal insulin doses based on the fasting BG results as usual. I still find it interesting that my insulin doses vary so much over time for reasons that I largely do not understand. Again, this is due to the very nature of exogenous insulin therapy and the effect of my exercise on insulin sensitivity.

Post 40 Insulin Dose Graph

I am omitting my Ketonix breath acetone results this month since I did not take any measurements in May.

In June, I will continue olympic weightlifting most days while trying to avoid injury and overtraining (by adjusting the load (intensity times repetitions) up or down) and do aerobic exercise (swimming, rowing, walking, or cycling at low intensity for ≈ 0.5 – 2 hours) the remainder of the days.

My Thoughts About Management of Type 1 Diabetes With A Ketogenic Diet

My goal of glycemic management in T1DM with a ketogenic diet is to keep BG as close to normal i.e. 96 ± 12 mg/dl (mean ± SD) as is safely possible (i.e. avoiding hypoglycemia) to avoid diabetic complications, a reduction in lifespan, and unpleasant symptoms of as well as injury and death from hypoglycemia. For me, a well-formulated whole-food nutrient-dense ketogenic diet (see blog post #9 for more details), daily exercise, frequent BG measurements, and lower insulin-analog doses (Humalog/Lantus) have improved my glycemic control, hypoglycemic reactions, and quality of life. My current version of ketogenic diet has changed slightly since I last wrote about it in detail in blog post #9. Since that post, I have eliminated dairy and decreased my fat intake to further improve my body composition so as to be able to compete in masters olympic weightlifting in the 77 kg weight class without having to think about when and how much I eat before weigh-in.

My current diet looks like this.

What I Cook & Eat

•Beef, grass-fed, including meat (85% lean), heart, liver, and kidney (liverwurst)

•Fish, mainly wild Alaskan salmon

•Canadian bacon (uncured)

•Lamb occasionally

•Chicken & Turkey occasionally

•Eggs (from chicken)

•Non-starchy vegetables (about 5% carbohydrate content by weight) including Cabbage (Red, Green, Napa), Kale, Collard Greens, Spinach, Bell Peppers, Raw Carrots, Leeks, Onions, Brussels sprouts, Home-made Sauerkraut from Red Cabbage, Bok-Choy, Broccoli, Cauliflower, Yellow Squash, Zucchini, Cucumber, Lettuce (Iceberg & Romaine), and some others.

•Fruit – Avocado, Tomatoes, Olives, Strawberries, Blueberries, Blackberries, lemon juice on fish and salads

•Nuts & Seeds – Pepitas, Macadamia, Brazil, Pecan, Walnut, Pistachio, Cashew.

•Note: I developed an intolerance to milk prior to my diagnosis of T1D. I did try heavy whipping cream after starting my KLCHF diet, but am also intolerant of it. I do tolerate butter, but wanted to decrease my fat intake, so eliminated all dairy including cheese and yogurt.

What I Drink

Water (filtered by reverse osmosis), Unsweetened Tea & Coffee

What I Don’t Eat

•Grains – Wheat, Corn, Rice, Oats (there are many more) or anything made from them, which is too numerous to list here. Gluten is a protein present in a number of grains (all varieties of wheat including spelt, kamut, and triticale as well as barley and rye.) which can cause a number of medical problems for a significant portion of the population with gluten sensitivity or celiac disease. In my case, I avoid them due to their carbohydrate content.

•Starchy vegetables – potatoes, sweet potatoes, yams, most root vegetables (turnip root okay), peas

•Legumes – peas, beans, lentils, peanuts, soybeans

•High sugar fruits – includes most fruits except berries, see above.

•Sugar and the fifty other names used to disguise sugar.

•Vegetable Oils (really seed oils) – Canola, Corn, Soybean, Peanut, Sunflower, Safflower, Cottonseed, Grape seed, Margarine & Butter substitutes, Shortening.

•All Processed Food-like Substances i.e., most of what is in the grocery store.

•I avoid restaurants except when traveling, and then order fish or steak with plain steamed non-starchy vegetables (no gravy or sauces that typically contain sugar, cornstarch, or flour) or salad.

•Refined, but healthy, Fats – I have eliminated refined fats from my diet including butter, coconut & olive oils.

What I Don’t Drink

•Colas (both sweetened and unsweetened).

•Fruit Juice except small amounts of lemon juice.

•Alcohol (can cause hyperglycemia or hypoglycemia in persons with diabetes).

•No artificial sweeteners, don’t need or like them.

A large part of my fat intake comes from nuts & seeds which hypothetically could result in potential adverse consequences from omega-6 polyunsaturated fats in the opinion of some low carb advocates. However, I have yet to see any studies that show harm from eating nuts & seeds. As a reference, the average fat breakdown of the seven nuts & seeds that I eat daily is 33% polyunsaturated, 52% monounsaturated, and 15% saturated fat. However, when my entire diet is analyzed, 26% of my fat intake is from polyunsaturates, 56% is from monounsaturates, and 18% is from saturated fats. When my diet is broken down by macronutrients, I consume 170 grams of fat (or 68% of my total daily calories), 70 grams of carbohydrate, 30 grams of which is dietary fiber (or 12% of my total daily calories), and 110 grams of protein (or 20% of my total daily calories). In calories, it totals to 2,250 kcal/day.

My exercise regimen and its resulting varying insulin sensitivity and hormonal changes actually makes glycemic management more difficult i.e. challenging, but I enjoy exercise and feel it has other health and lifespan-extending benefits. Hopefully, my BG values and variability as well as my lower insulin doses that result from my ketogenic diet and exercise are close enough to optimal to avoid any reduction in lifespan, diabetic complications, and harm from hypoglycemia. Only time will tell.

Till next time …

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2 comments

  1. Alex Romayev

    Hi Keith,

    I was wondering if you had more information or just had an opinion on the MGM trial that’s about to go into phase II clinical trials (http://www.faustmanlab.org)? It seems that the vaccine is able to restore at least some beta cell function and (my thinking) in combination with a ketogenic diet, might just be enough to significantly reduce if not completely avoid the need for injections.

    Thanks,
    -Alex

    Like

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