Regulation of blood glucose in the human body
Glucose is the primary fuel source for almost all cells of an organism, except for cardiac muscle between meals; skeletal muscle at rest and adipose tissue which utilize fatty acids. Therefore, blood glucose homeostasis is important to ensure normal function and survival of the organism. It is tightly regulated between three interrelated processes: glucose uptake and utilization of tissues which is mainly controlled by insulin; glucose production in the liver and the action of counter-regulatory hormones1.
The blood glucose level is maintained within a narrow range of 80 to 100 mg/dl (4.5- 5.5 mmol/l) in the fasting state and brought back to this level after a transient post- prandial rise (the peak of which never reaching the renal threshold of 10 mmol/l in normal persons). The metabolic processes which maintain this level are those which bring it down (glycolysis, glycogenesis, lipogenesis, inhibition of gluconeogenesis) and those which raise it (inhibition of glycolysis, glyconeolysis, gluconeogenesis). Insulin is the only hypoglycaemic hormone in the body, released from the beta cells of the islets of Langerhans in the pancreas when the blood glucose level rises i.e. after meals. Between meals, glucagon causes liver glycogen to be broken down into glucose (muscle glycogen cannot be broken down), this process being sufficient to provided glucose for a few hours (around 6 hours in people on a normal carbohydrate diet). After the liver glycogen has been used up, glucose is produce by gluconeogenesis in the liver and kidneys, stimulated by the diabetogenic hormones (glucagon, growth hormone, epinephrine, and cortisol). Gluconeogenic substrates include glycerol, lactate, propionate, and certain amino acids.
The role of the pancreas
The main hormones of the pancreas that affect blood glucose include insulin, glucagon, somatostatin, and amylin. Insulin (formed in the pancreatic beta cells) lowers blood glucose levels, whereas glucagon (from the pancreatic alpha cells) elevates it2. Somatostatin (formed in the delta cells of the pancreas) balances insulin and glucago, turning on or turning off each opposing hormone. Amylin is a hormone, made in a 1:100 ratio with insulin that helps increase satiety, or satisfaction and state of fullness from a meal, to prevent overeating. It also helps slow the stomach contents from emptying too quickly, to avoid a quick spike in blood glucose levels.
Insulin The rise in blood glucose level after meals stimulates insulin release from the stored vesicles in a complex process which involves many proteins for stimulation, vesicle fusion and exocytosis. Glucose taken up into and broken down by the beta cells leads the opening of calcium ion channels that results in the release of insulin into the blood. External factors affecting pancreatic insulin release via metabolic-cAMP coupling are glucagon-like peptide 1 and glucose dependent insulinotropic peptide.
Glucose uptake by the cells is through recruitment of glucose transporter GLUT4 which involves phosphorylation of tyrosine residues of specific proteins. This is mediated by a signaling cascade after insulin binds to its receptor (tyrosine kinase receptor) present on the cell membrane. Insulin also effects a range of cellular responses including activation and induction of proteins involved in carbohydrate, lipid and protein metabolism. Insulin exerts its hypoglycaemic effects through (a) glucose utilization for energy in nearly all cells by promoting glycolysis (b) stimulation of glycogenesis in the liver and muscle. Liver glycogen serves as a source of glucose for use in- between meals (c) activation of lipogenesis of adipose tissue and liver; therefore, acting as an anabolic hormone.
Glycogen – Glucagon and other hyperglycemic hormones maintain blood glucose levels when it is low and in-between meals and during sleep .Upon reaching the liver, glucagon binds to its specific G- protein linked receptor to activate hepatic glycogen breakdown, thereby increasing the blood glucose level. It also drives hepatic and renal gluconeogenesis from amino acids and glycerol release from adipose triglyceride breakdown. This process maintains blood glucose level in prolonged fasting.
Regulation-blood-glucose3
The Role of Incretins4
Incretins are glucagon-like peptides (hormones) made in cells of the small intestine and secreted into the circulation in response to food intake. Incretins go to work even before blood glucose levels rise following a meal. They also slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying, and they may also help decrease food intake by increasing satiety.
Two types of incretin hormones are GLP-1 (glucagon-like peptide) and GIP (gastric inhibitory polypeptide). Each peptide is broken down by naturally occurring enzymes called DDP-4, (dipeptidyl peptidase-4).The functions of incretins are as follows:
- Stimulate insulin secretion
- Suppress glucagon secretion
- Slow gastric emptying to prevent spike in BG levels
- Increase satiety after a meal to signal to the brain to stop eating
People with type 2 diabetes have lower than normal levels of incretins, which may partly explain why many people with diabetes state they constantly, feel hungry. After research showed that BG levels are influenced by intestinal hormones in addition to insulin and glucagon, incretin mimetics became a new class of medications to help balance BG levels in people who have diabetes.
Glucocorticoids
Another hormone involved in glucose homeostasis is glucocorticoid, a steroid hormone released from adrenal cortex during stress. It promotes hepatic gluconeogenesis, reduce glucose uptake and utilization in skeletal muscle and white adipose tissue. These effects are critical for metabolic adaptation during stress, such as fasting or starvation.
Insulin resistance and diabetes mellitus
Impaired insulin secretion from pancreatic beta cells or impaired signaling of insulin in the cells with poor response of cells to insulin may cause diabetes mellitus. As a result the cells are less able to take up glucose from the blood. The body produces more insulin than it is normally needed to overcome this resistance. It is well documented that insulin resistance is strongly associated with obesity, genetics and aging. It is also common in people with unhealthy lifestyle, low quality nutrition and smoking.
Diabetes mellitus
The American Diabetes Association regards Diabetes mellitus as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.
In type 1 diabetes, the body produces insufficient insulin form beta cells to regulate blood glucose level. They also lack amylin production. Most cells are unable take up and utilize glucose and use fatty acids as an alternative source of energy. Consequently, ketones are produced more by the liver, and may lead to ketoacidosis. Therefore, people with type 1 diabetes will need to inject insulin to compensate for their body’s lack of insulin.
In Type 2 diabetes is one of the most common health problems in human and is a major public health problem there is hyperglycemia with the production of normal level or a relative high level of insulin. In the early part of the disease, the body does not respond well to insulin and in the later stages the exhausted pancreas produces less and less insulin. People with Type 2 diabetes seem to make adequate amounts of amylin but often have problems with the intestinal incretin hormones that also regulate BG and satiety, causing them to feel hungry constantly. Amylin analogues have been created and are available through various pharmaceutical companies as a solution for disorders of this hormone.
Pathogenesis of Type 2 diabetes is complex and involves the interaction of genetic, life style and environmental factors. However, the precise mechanisms by which these factors interact to lead to the Type 2 diabetes are not known. A consistent observation is that they demonstrate three characteristics: resistance to the action of insulin, defective insulin secretion and increased glucose production by the liver. Insulin resistance indicates the presence of an impaired biologic response to insulin. It leads to decreased glucose transport into adipocytes and myocytes, and increased adipocyte lipolysis. When insulin resistance develops in the insulin sensitive tissues, the beta cell increases insulin secretion to maintain the normal glucose level. Over time, the beta cells are incapable of increasing insulin secretion, the blood glucose levels become elevated. As beta cell dysfunction progresses, further elevation of glucose occur and diabetes is the eventual result.
A complex interplay of hormones have been suggested for the development of insulin resistance and a number of hormones been implicated. Among them are ghrelin5, leptin6 andasprosin7. Leptin and ghrelin are also linked to regulation of food intake and lipogenesis. The most recently proposed is asprosin, a novel glucogenicadipokine, encoded by two exons (exon 65 and exon 66) of the gene Fibrillin 1 (FBN1) and mainly synthesized and released by white adipose tissue during fasting. Asprosin plays a complex role in the central nervous system peripheral tissues, and organs.
Diagnosis of Diabetes
It rests on the measurement of glycaemia; fasting blood glucose, 2-hour plasma glucose, and glycated hemoglobin A (HbA1c).HbA1c is a modified Hb A1. When haemoglobin is exposed to high blood sugar for long periods, glucose attaches to Hb and later becomes stabilized. This process is enzyme independent.
Plasma HbA1c is now measured for the diagnosis of diabetes. HbA1c level in blood reflects the glycemic level for the previous 6 to 8 weeks and its level is also able to predict the presence of retinopathy.
A major risk for the development of Type 2 diabetes are overweight / obesity, first degree relatives with diabetes, physical inactivity, hypertension and d hyper triglyceridemia and hyper cholesterolaemia.
Metabolic syndrome
Metabolic syndrome is defined by a constellation of interconnected physiological, biochemical, clinical, and metabolic factors that directly increases the risk of cardiovascular disease, Type 2 diabetes mellitus, and associated with mortality.
Metabolic syndrome is a group of symptoms of metabolic derangements, commonly seen in patients with insulin resistance, and is associated with an increased risk of cardiovascular disease. These derangements are termed metabolic syndrome, insulin resistance or diabetes mellitus, obesity, hypertension, dyslipidemia.
The exact molecular basis of metabolic syndrome is not clear but many researchers are elucidating on this matter. Many proposed that the central of it is insulin resistance which is closely related with obesity. Yet, there are many other precipitating factors such as smoking and viral infection.
Visceral obesity and insulin resistance associated with the production of inflammatory mediators such as tumor necrosis factor α, interleukin-1 (IL-1), IL-6, leptin, and adiponectin. They contribute to the development of a proinflammatory state and further a chronic, subclinical vascular inflammation which modulates and results in atherosclerotic processes.
Diagnosis of metabolic syndrome proposed by the International Diabetes Federation (IDF) is based on the modification of the World Health Organization definition and Adult Treatment Panel III criteria. According to the IDF definition, individuals are diagnosed as having Metabolic Syndrome if they have central obesity (waist circumference of ≥ 94 cm for men and ≥ 80 cm for women) and any two of the following factors: elevated triglycerides (≥ 150 mg/dL), decreased HDL cholesterol (< 40 mg/dl) in males and < 50 mg/dl in females), hypertension (systolic ≥ 130 mmHg or diastolic ≥ 85 mmHg) and raised fasting plasma glucose (≥ 100 mg/dl). Pharmacological intervention together with life style changes and exercise will reduce the risk factors.
References
- Williams Text Book of Endocrinology, 13th Edition (2015) ELSERVIER, pp1386-1407https://www.diabetes.co.uk/body/insulin.html
- Röder VP, Wu B, Liu Y and Han Y. (2016) Pancreatic regulation of glucose homeostasis. Experimental and Molecular Medicine 48, e219.
- https://www.atrainceu.com/content/4-regulation-blood-glucose
- Cernea S, Raz I. (2011). Therapy in the Early Stage: Incretins. American Diabetes Association. Diabetes Care 34(supp 2):S264–71 doi: 10.2337/dc11-s223. Retrieved
- Chabot F, Caron A, Laplante N & St-Piere DH ( 2014). Interrelationships between ghrelin, insulin and glucose homeostasis: Physiological relevanceWorld J Diabetes. 5(3): 328–341
- Osegbe I, Okpara H and AzingeE( 2016). Relationship between serum leptin and insulin resistance among obese Nigerian women.AnnAfr Med. 2016 Jan-Mar; 15(1): 14–19.
- Yuan M, Li W, Zhu Y, Yu B and Wu J ( 2020) Asprosin: A Novel Player in Metabolic Diseases
Endocrinol (Lausanne)vol.11; 2020 PMC7045041
