Metformin's Effect Linked Strongly to Activation of AMPK

Page changed: Metformin

Included findings of a fascinating study published in 2001, but previously overlooked, that provided detailed insight into Metformin's activation of AMP-kinase (AMPK) in rat tissue in ways that provide explanations for many of the anecdotally observed effects of Metformin that are not directly related to insulin resistance, most notably its ability to prevent weight regain in dieters and the way it appears to lower glycogen stores. Another study is cited that describes cardioprotective effects of the activation of AMPK that may explain metformin's observed cardioprotective effects.

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Metformin's Activation of AMPK Blocks The Liver's Ability to Synthesize Triglycerides and Promotes Fat Burning.

For an exhaustive look at how metformin's impact on AMP-kinase works in rat tissues (and probably human tissues), read this full text study:

Role of AMP-activated protein kinase in mechanism of metformin actionZhou et al. J. Clin. Invest. 108(8): 1167-1174 (2001). doi:10.1172/JCI13505.

This study found that

metformin activates AMPK in hepatocytes [liver cells]; as a result, acetyl-CoA carboxylase (ACC) activity is reduced [ACC promotes the creation of triglycerides], fatty acid oxidation is induced [i.e. fat is burned], and expression of lipogenic enzymes is suppressed [lipogenic enzymes are needed to create triglycerides].

It also found that glucose uptake in muscles by metformin required the activation of AMPK. When it was blocked the uptake did not happen.

AMPK activation is also known to increase the breakdown of glycogen, which may be why some low carbers have observed that their glycogen stores appear already depleted when they embark on a low carb diet, so they don't lose the glycogen-associated water weight at the start of the diet that dieters lose who are not taking metformin. It may also be why when theu carb up they don't gain a lot of instant water weight either.

It is this impact of metformin on the liver, which is independent of its impact on glucose absorption that probably explains why metformin often causes modest weight loss, especially when it is first taken. It also explains why it makes weight loss maintenance much easier even in insulin sensitive dieters such as myself. Blocking the synthesis of fats and promoting the burning of fat at the liver (and possibly muscles) makes it much harder to gain weight.

Stimulation of AMPK May Be Why Metformin Appears Cardioprotective

AMPK has also been shown to have a protective effect on the heart. This review describes how AMPK may protect the body during heart attacks.

AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Lawrence H. Young. Circulation. 2008;117:832-840 doi: 10.1161/CIRCULATIONAHA.107.713115

More Evidence Lean Offspring of People With Type 2 Show Beta Cell Defects and IR

Page Changed: You Did Not Eat Your Way to Diabetes

A new study published in Diabetologia confirms the finding of an earlier study that shows that lean, young relatives of people with Type 2 diabetes already show dramatic differences in their ability to secrete insulin and their insulin sensitivity.

This points out very clearly that people who develop diabetes didn't cause their disorder by overeating, as they already have high post-meal blood sugars when young and thin. This is attributed in the study to beta cell dysfunction.

This study compared detailed measurements of insulin secretion and resistance in 187 offspring of people diagnosed with Type 2 diabetes against 509 controls. Subjects were matched with controls for age, gender and BMI. It concluded:

The first-degree offspring of type 2 diabetic patients show insulin resistance and beta cell dysfunction in response to oral glucose challenge. Beta cell impairment exists in insulin-sensitive offspring of patients with type 2 diabetes, suggesting beta cell dysfunction to be a major defect determining diabetes development in diabetic offspring.

Beta cell (dys)function in non-diabetic offspring of diabetic patients M. Stadler et al. Diabetologia Volume 52, Number 11 / November, 2009, pp 2435-2444. doi 10.1007/s00125-009-1520-7

NHANES: Retinopathy Incidence Rises Steeply At 5.5% A1c

Page Changed: Research Connecting Organ Damage with Blood Sugar Level

Added analysis of 2005-2006 NHANES data which was published in October 2009. The study looked at 1,066 individuals with or without diabetes aged 40 years or more. "A1C, FPG, and 45° color digital retinal images were assessed."

This study found a prevalence of retinopathy of 11% in those diagnosed with diabetes and 36% in those with diabetes diagnoses.

Most significantly, this study found that

The steepest increase in retinopathy prevalence occurs among individuals with A1C equal to or greater than 5.5% and FPG equal to or greater than 5.8 mmol/l [104 mg/dl]. A1C discriminates prevalence of retinopathy better than FPG.

Association of A1C and Fasting Plasma Glucose Levels With Diabetic Retinopathy Prevalence in the U.S. Population: Implications for diabetes diagnostic thresholds Yiling J. Cheng et al. Diabetes Care November 2009 vol. 32 no. 11 2027-2032. doi: 10.2337/dc09-0440

Sulfonylurea Drugs Linked to Hemolytic Anemia Especially with Certain Genetic Condition

Page Changed: Amaryl, Glyburide, Prandin, Starlix: Drugs that Stimulate Insulin Secretion

Added information on new FDA Safety Alert.

An FDA safety Alert published Auguest of 2009 reports:

Treatment of patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea agents can lead to hemolytic anemia. Because Glynase PresTab belongs to the class of sulfonylurea agents, caution should be used in patients with G6PD deficiency and a non-sulfonylurea alternative should be considered. In post marketing reports, hemolytic anemia has also been reported in patients who did not have known G6PD deficiency.

Hemolytic anemia is a condition where the body stops making red blood cells. It can become an emergency. Symptoms of hemolytic anemia include Dark urine, Enlarged spleen, Fatigue, Paleness, Rapid heart rate, Shortness of breath, Yellow skin color (jaundice).

Because the G6PD deficiency is often only discovered when people react badly to a drug, it would be a good idea to get your blood count tested shortly after starting a sulfonylurea drug.

FDA Safety Alert for Glynase (micronized glyburide) tablets

Metformin Fights Heart Disease by Improving Endothelial Function

Page changed: Metformin

Added section discussing the latest studies documenting Metformin's ability to prevent heart disease by improving endothelial function.

This idea has been floating around for years, though there wasn't definitive proof of it. A relatively small study published in March 2009 supports the idea.

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus. Kooy et all. Archives of Internal Medicine, 169 (6), 616-625 DOI: 19307526

A presentation at the 2009 European Association for the Study of Diabetes (EASD) described research which may point to why metformin is so effective.

You can read about it here:

Diabetes in Control: Metformin Improves Endothelial Function in Type 2 Diabetes

This study examined a series of factors associated with endothelial function--i.e. the function of the linings of the blood vessels. It demonstrated significant improvements in the 196 patients who took metformin over a period of up to 4.3 years.

Compared to those on placebo plus insulin those on metformin experienced highly significant drops in plasma levels of von Willebrand factor (vWf), soluble vascular adhesion molecule-1 (sVCAM-1), tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1).

The drop in C-Reactive Protein--a measure strongly linked to the risk of inflammation-related heart attack was 17%.

Since all the other oral drugs prescribed for diabetes have either been linked to increased heart attacks (sulfonylureas) or produce heart failure (Avandia and Actos) this data should reinforce the idea that metformin is the safest of the oral diabetic drugs and the one most likely to improve health outcomes long term.

FDA Adds Pancreatitis Warning to Januvia and Janumet Prescribing Information

Page changed: Januvia

Added information that FDA has added a warning about the association of pancreatitis with Januvia, including the information that "Furthermore, 47 of the 88 cases (53%) resolved once sitagliptin was discontinued."

Doctors are advised to warn patients prescribed Januvia of the symptoms of pancreatitis so they can be taken off the drug.

If you are on Januvia, has your doctor warned you about the symptoms of pancreatitis? If not, ask your doctor why. The doctor probably doesn't know of this latest issue with Januvia, as they usually don't know of the others, either.

Added Fish Oil to The "Helpful Supplements" Page

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Added the text from today's Diabetes Update blog post, Fish Oil Yes--But Not From Fish , to the web page about helpful supplements.