Running DMC: Diabetes, Metformin and Carbs.


Type 2 Diabetes, Metformin & Carbs
Q: “In the context of type 2 diabetes, metformin reduces the amount of sugar released into the bloodstream by the liver after a meal, but what happens to the unreleased sugar/carbs? Does it get converted to fat and stored or is passed out as feces?”

A: Let’s begin with understanding the pathology in question and the mechanism of metformin’s action.

What is the problem here?


Diabetes (both types 1 and 2) turns the body into a predominantly catabolic state (as insulin is anabolic in nature). This means that for the cells of your body to get the fuel they need, the liver revs up synthesis of glucose from non-carbohydrate sources (amino acids, lipids), as glucose that has been absorbed from food is not entirely available for glycolysis and subsequent utilisation.

glycolysis steps
Figure 1: Glycolysis - breakdown of available glucose into pyruvic acid, which can be utilised for cellular function. Source: https://www.checkdiabetes.org/glycolysis/
The problem here is that because glucose in the bloodstream cannot essentially be utilised, it accumulates there, causing what we call ‘high blood sugar’. This high blood sugar can damage various organs in the body (kidneys, eyes, nerves, blood vessels etc) in the long run, so it needs to be controlled.

Image result for effects of high blood sugar
Figure 2: The effects of chronic hyperglycemia on different organs of the body. Source: https://www.skyterrawellness.com/wellness/infographic-your-body-on-sugar/

Since the pathology in type 2 diabetes is essentially a resistance to insulin, giving more insulin isn’t the best option to go with; treatment strategies primarily involve lowering that resistance; with ‘overpowering the system with insulin’ being a last resort. This is where oral hypoglycemic agents like metformin come in.

Metformin and How It Acts


Metformin is a drug used in diabetes and polycystic ovarian syndrome that belongs to the biguanide class of drugs originating from the French lilac plant, and it first became available to the world between the 1960s and the 1990s.
How it works is two-fold:
a. By increasing the body’s sensitivity to insuli
b. By suppressing gluconeogenesis (the synthesis of glucose from non-carbohydrate sources in the liver) and glycogenolysis (breakdown of glycogen into glucose-6-phosphate, which is available for glycolysis) – but the suppression effect on gluconeogenesis is far bigger than that on glycogenolysis.

Antihyperglycemic action of metformin. Metformin ameliorates hyperglycemia and enhances insulin sensitivity through the suppression of gluconeogenesis and glycogenolysis in liver, stimulation of glucose uptake in muscle, suppression of free fatty acid (FFA) and reduction of intestinal absorption of glucose.  
Figure 3: Metabolic effects of metformin. Source: Correia S, Carvalho C, Santos M, Seica R, Oliveira C, Moreira P. Mechanisms of Action of Metformin in Type 2 Diabetes and Associated Complications: An Overview. Mini-Reviews in Medicinal Chemistry. 2008Jan;8(13):1343–54.
Let’s examine them in more detail.

Increasing Insulin Sensitivity


This action of metformin is associated with several mechanisms, such as:
a. Increased insulin receptor tyrosine kinase activity
b. Enhanced glycogen synthesis
c. Increase in the recruitment and activity of GLUT4 glucose transporters
d. Promotion of re-esterification of free fatty acids in adipose tissue and inhibition of lipolysis - which may indirectly improve insulin sensitivity through reduced lipotoxicity.

Suppressing Gluconeogenesis and Glycogenolysis


If you look at the effect metformin has on gluconeogenesis, it essentially opposes the conversion of non-carbohydrate molecules into carbohydrates. Since the starting points of gluconeogenesis are amino acids and lipids, there is no question of ‘unreleased carbs’.
However, metformin also mildly suppresses glycogenolysis. The starting point of this breakdown is, of course, glycogen. Hence, the use of metformin promotes carbs to stay in their natural ‘storage form’ as glycogen, as opposed to being converted into monosaccharides.

The Long and Short of It


So, to answer the original question, glucose that is made available from the liver in type 2 diabetes comes from both carbohydrate and non-carbohydrate sources – both of which are inhibited by metformin. The primary effect of metformin is lowering the conversion of non-carbohydrate molecules to carbohydrates. In addition, the process of glycogenolysis is also inhibited by metformin to a smaller extent – mildly promoting the carbohydrates of the body to stay in the form of glycogen. It does not promote the removal of carbohydrates from the body through urine, feces, sweat or any other bodily fluids.

By Dr Anmol Dhawan

References:

1. Correia S, Carvalho C, Santos M, Seica R, Oliveira C, Moreira P. Mechanisms of Action of Metformin in Type 2 Diabetes and Associated Complications: An Overview. Mini-Reviews in Medicinal Chemistry. 2008Jan;8(13):1343–54.
2. Giannarelli R, Aragona M, Coppelli A, Prato SD. Reducing insulin resistance with metformin: the evidence today. Diabetes & Metabolism. 2003;29(4).
https://www.checkdiabetes.org/glycolysis/ (image)
https://www.skyterrawellness.com/wellness/infographic-your-body-on-sugar/ (image)
3. https://www.checkdiabetes.org/glycolysis/
4. https://www.skyterrawellness.com/wellness/infographic-your-body-on-sugar/ (image)

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