This literature review does not constitute medical advice.
Type 2 Diabetes Mellitus (T2DM) is the result of poor glucose metabolism due to insulin resistance and the dysfunction of pancreatic β-cells, causing increased levels of blood glucose (hyperglycaemia) (1). Glucose metabolism involves the breakdown of primarily carbohydrates via glycolysis and oxidative phosphorylation for energy, as well as production of glycogen via glycogenesis for the body to use as energy storage (2). Glucose can also be synthesised via the process of gluconeogenesis where sources including pyruvate, glycerol, amino acids, and lactate can be used when inadequate amounts of carbohydrates are consumed.
Glucose metabolism in Type 2 Diabetes
Glucose metabolism is altered in the pancreas, liver, gastrointestinal system, nervous system, adipocytes, and skeletal muscles of people with T2DM (2).
In a healthy human, the pancreas secretes the hormone insulin, produced by β-cells, when high concentrations of glucose occur in the blood to drive glucose into the intracellular environment of cells for the uptake and utilization of energy (2). When blood glucose levels fall, glucagon is secreted for activation of glycogenolysis and gluconeogenesis to regulate glycaemic levels. People with T2DM have reduced amount of insulin sensitivity upon ingestion of carbohydrates, causing an increased amount of glucose to circulate in the blood. This promotes the pancreas to continue secreting insulin, where overtime the body will have reduced sensitivity to insulin if it continues to be produced at a large rate (2).
The liver acts as storage for glycogen, and in healthy humans it regulates intake and output of glucose (2). In the fed state, glucose is converted into glycogen and stored in the liver, while in the fasted state, glucose is released into the bloodstream at a steady state as required by cells. People with T2DM often experience impaired glucose homeostasis, placing them at risk of liver disease such as hepatic steatosis (fatty liver disease), contributing to decreased regulation of glucose in the liver (3).
The hypothalamus will sense low blood glucose levels and activate the sympathetic nervous system for increased control (2). The brain uses glucose as its primary fuel source for actions including generation of neurotransmitters and ATP. Irregular glucose metabolism as a result of T2DM has been linked to cognitive impairments in the brain (4).
In a healthy human, insulin is secreted causing glucose uptake and utilisation by adipocytes to increase (5). However, people with T2DM experience reduced glucose uptake by adipocytes due to insulin resistance. Adipocytes influence glycaemic control, and alterations of adipocytes through conditions such as obesity can disrupt glucose homeostasis, causing insulin resistance and hyperglycaemia (5).
People with T2DM will experience reduced uptake of glucose in skeletal muscle and insulin resistance due to a defect in signalling to GLUT4, a glucose transporter (6). This results in less energy in the skeletal muscles and overtime can cause muscle atrophy (6).
Post-prandial metabolism in people with T2DM compared to non-diabetic individuals
Post-prandial metabolism of a given load of digestible carbohydrates will begin digestion and absorption in the oral cavity and stomach into a smaller molecule known as glucose (2).
Glucose enters the blood stream via the liver to provide cells with energy, and simultaneously, insulin is secreted from the pancreas to assist cells with the uptake of glucose. If blood glucose levels are high, the liver acts as a storage of glycogen until glucagon is released from the pancreas to stimulate the synthesis glucose and breakdown of glycogen for the cells to use for energy (2).
People with diabetes have an altered post-prandial glucose metabolism experience due to the resistance to and deficiency of insulin (2). Digestion of carbohydrates in the oral cavity and stomach into glucose is the same in both diabetic and non-diabetic individuals. Due to this dysfunction of β-cells, a deficiency of insulin is released upon glucose entering the liver and bloodstream, causing blood glucose levels to increase in the fed state from carbohydrate consumption and in the fasted state through synthesis of new glucose (gluconeogenesis). An insulin resistance occurs in people with T2DM and glucose uptake in the cells is diminished, contributing to this increase in blood glucose levels (2).
The key difference in post-prandial glucose metabolism between non-diabetic and diabetic individuals is that non-diabetic people can regulate their blood glucose levels with the assistance of insulin whereas people with T2DM lack sufficient insulin sensitivity to properly regulate glycaemic levels (2).
Very low carbohydrate diet (VLCD) compared to high carbohydrate diet (HCD) in terms of glucose metabolism
In the observance of a VLCD, the glucose related metabolic pathways are different compared to a much higher carbohydrate content diet, particularly in the levels of insulin secretion (7, 8). In the absence or restriction of carbohydrates, the body will begin synthesizing glucose from other sources (7). Lactate, pyruvate, glycerol from fat stores, and amino acids from muscles can be used to produce glucose via gluconeogenesis. After approximately four days of restricted carbohydrate intake of less than 50g, the body’s glycogen stores will deplete, forcing fat to take over as the body’s fuel source. The body will enter the state of ketosis where the liver will convert fat into fatty acids and ketones for fuel. As a result, the VLCD will decrease the amount of insulin secreted by the pancreas as minimal glucose is required to be regulated in the blood (7).
A diet where carbohydrate intake is increased to more than 60% of total daily macronutrient intake is considered a HCD (8). Ultimately, increasing carbohydrate intake will increase blood glucose levels and hyperinsulinemia (excess insulin in blood compared to blood glucose) in attempt to regulate the glucose. These mechanisms lead to increased hunger and fatigue as there is a decrease in the metabolic circulation of glucose (8).
The quality of the carbohydrate food source when consuming a HCD contributes to differences in glucose metabolism and can be measured based on the glycaemic index (GI) (9). Refined carbohydrates (high GI) such as white bread, cakes, and potatoes are absorbed rapidly by the body and cause a spike in blood glucose levels and insulin secretion, therefore increasing risk of insulin resistance. Fibre rich, low GI foods such as grains and vegetables support a sustained release and breakdown of the carbohydrates which help to decrease insulin resistance and promote steady blood glucose levels post-prandial (9).
Efficacy of very low carbohydrate diet in improving glucose control in people with Type 2 Diabetes
VLCD have been studied for improving glucose control in people with T2DM (10,11). With inadequate amounts of carbohydrates as a primary food source, the body goes into a state of ketosis where fats and ketones take over (7). Restriction of carbohydrates causes a decrease in blood glucose levels and insulin secretion, enhancing glycaemic control (10,11). A VLCD often places the patient in a calorie deficit which causes them to lose weight, a contributing factor in improving insulin resistance. Research suggests people with T2DM who consume a VLCD had reductions in the use of diabetic medication to control glycaemic levels, suggesting high efficacy of the diet. However, adherence to a VLCD can be difficult due to the high restrictive nature and possible side effects including lack of energy and mental fatigue (10,11).
Evidence suggests the effects of a VLCD on T2DM are promising in the control of blood glucose levels and increased insulin sensitivity (12). With lower blood glucose levels in the body, insulin secretion levels are also lowered, which overtime can reduce the prevalence of insulin resistance. People with T2DM who followed a VLCD consisting of carbohydrate consumption at less than 26% of total daily intake had increased management of diabetic symptoms and metabolic mechanisms (12).
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(2) Nakrani NM, Wineland RH, Anjum F. Physiology, glucose metabolism. StatPearls.
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(4) Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013 Oct;36(10):587-97. 10.1016/j.tins.2013.07.001
(5) Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006 Dec 14;444(7121):847-53. 10.1038/nature05483
(6) Chadt A, Al-Hasani H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 2020 Sep;472(9):1273-1298. 10.1007/s00424-020-02417-x
(7) Merrill JD, Soliman D, Kumar N, Lim S, Shariff AI, Yancy WS. Low-carbohydrate and very-low-carbohydrate diets in patients with diabetes. Diabetes Spectr. May 2020;33(2):133-142. doi.org/10.2337/ds19-0070
(8) Jung CH, Choi KM. Impact of high-carbohydrate diet on metabolic parameters in patients with type 2 diabetes. Nutrients. 2017 Mar 24;9(4):322. 10.3390/nu9040322
(9) Vega-López S, Venn BJ, Slavin JL. Relevance of the glycemic index and glycemic load for body weight, diabetes, and cardiovascular disease. Nutrients. 2018 Sep 22;10(10):1361. 10.3390/nu10101361
(10) Bolla AM, Caretto A, Laurenzi A, Scavini M, Piemonti L. Low-carb and ketogenic diets in type 1 and type 2 diabetes. Nutrients 2019 April;11(5):962. 10.3390/nu11050962
(11) Gupta L, Khandelwal D, Kalra S, Gupta P, Dutta D, Aggarwal S. Ketogenic diet in endocrine disorders: Current perspectives. J Postgrad Med. 2017 Oct;63(4):242-251. 10.4103/jpgm.JPGM_16_17
(12) Meng Y, Bai H, Wang S, Li Z, Wang Q, Chen L. Efficacy of low carbohydrate diet for type 2 diabetes mellitus management: A systematic review and meta-analysis of randomized controlled trials. Diabetes Research and Clinical Practice 2017;131:124-131. doi.org/10.1016/j.diabres.2017.07.006