Regulation of blood glucose level

By Sergey Skudaev


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A level of glucose in plasma depends on many hormones and factors. Some diabetic patients think that if they do not eat sugar or carbohydrates plasma glucose cannot be high. It is not true because the glucose enters plasma, not only from food, but also from liver glycogen or as a result of change in protein metabolism (gluconeogenesis ). Gluconeogenesis is the generation of glucose from amino acids or other substrates. Gluconeonenesis occurs in liver in fasting conditions or starvation, but we are not going to discuss starvation.

In fasting conditions, pancreas alpha-cells produce glucagon, a hormone that causes liver to release glucose from glycogen. It is a defense mechanism against hypoglycemia (a low level of glucose). Hypoglycemia stimulates brain stem and hypothalamus.[10]. This stimulation increases food intake [4] and inhibit insulin secretion. [3].

When food intake increases level of plasma glucose, beta-cells of pancreas Langerhans islets produce insulin and amylin, two hormones which decrease level of plasma glucose by different mechanisms.

A human has, approximately, 1-1.5 million of Langerhans islets. Reduction of this number by more than half impairs glucose regulation process.[4]

Insulin stimulates glucose utilization in skeletal muscles, heart and some other tissues. Also, it increases skeletal muscle blood flow which depends on release of Nitric Oxide (NO) by the endothelium of the muscular vessels. [5]. Increasing blood flow in muscles increases glucose utilization. Additionally, insulin suppresses secretion of glucagon from pancreatic alpha-cells and decreases release of glucose from liver.

The second hormone of pancreatic beta-cells, amylin, which was discovered in 1987 [10], inhibits glucagon secretion, regulates gastric emptying and decreases food intake.[5] Luck of amylin in diabetic patients impairs the glucose-regulating process.

Additionally to insulin deficiency, accelerated gastric emptying and increased food intake responsible for increasing level of plasma glucose in diabetic patients.

Insulin and amylin complement each other in glucose control by regulation of food uptake, inhibition of endogenous glucose and by increasing glucose utilization by insulin-sensitive tissues. Exercise increases glucose utilization by muscles and helps to decrease blood glucose level.

In healthy individuals, a greater insulin response is observed when glucose is consumed naturaly compared to administered introvenously[8]. The explanation of this fenomenon is that the gastrointestinal tract produces hormones which affect insulin secretion and glucose homeostasis.

The long term blood glucose level is measured by testing of HbA1c (glycosylated haemoglobin). The International Diabetes Federation (IDF) recommends testing of HbA1c every 2-6 months. Testing of HbA1c is very important tool in controlling blood glucose. According to Dr Kerstin Berntorp, member of the GTF on Glycaemic Control, Department of Endocrinology, Malmo University Hospital, Sweden, "Each 1% reduction in HbA1c decreases the risk of damage to the retina, kidneys and nerve function by 37%, and the risk of diabetes-related death by 20%."

Two important hormones affecting blood glucose level are: gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). GLP-1 is produced by the ileum and the colon in response to incoming nutrients. It increases insulin synthesis and glucose-dependent insulin secretion, inhibits glucagon secretion and delays gastric emptying. In animals, GLP-1 increases the mass of pancreatic beta-cells. GLP-1 receptors found in the hypothalamus and their stimulation decreases food intake

GLP-1 cannot be used for the treatment of diabetes because it is inactivated by DPP-IY enzyme.
A new promising drug exenatide was synthesed that is GLP-1 receptor agonist and mimics GLP-1 effects. In diabetic patients, injection of exenatide reduces postprandial glycemia and body weight.[6]

New promising grugs that inhibit DPP-IV enzyme and prolong GLP-1 effects that were synthesed recently are vidagliptin and sitagliptin. They improve insulin response and decrease glucagon level. [1][2]


References:

1. Ahren B. et al. Diabetes. 2003;52:A15 (Abstract 65-OR)

2. Aschner P, Kipnes M, Lunceford J, Mickel C, Davies M, Williams-Herman D. Sitagliptin Monotherapy Improved Glycemic Control in the Fasting and Postprandial States and Beta-Cell Function after 24 Weeks in Patients with Type 2 Diabetes (T2DM) ADA Abstract: 2006. Abstract Number: 1995-PO.

3.Blat S and Malbert CH. The vagus is inhibitory of insulin secretion under fasting conditions. Am J Physiol Endocrinol Metab 281: E782-E788, 2001.

4. Buijs RM, Chun SJ, Niijima A, Romijn HJ, and Nagai K. Parasympathetic and sympathetic control of the pancreas: a role for the suprachiasmatic nucleus and other hypothalamic centers that are involved in the regulation of food intake. J Comp Neurol 431: 405-423, 2001

5. Denis Roy, Mylène Perreault, and André Marette. Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent. Am J Physiol Endocrinol Metab 274: E692-E699, 1998;

6. Drucker D.J. Enhancing incretin action for the treatement of type 2 diabetes. Diabetes Care 2003;26:2929-2940.

7. Manley S. Haemoglobin A1c - a marker for complications of type 2 diabetes. The experience from the UK Prospective Diabetes Study (UKPDS). Clin Chem Lab Med 2003; 41:1182-90

8. Melvin R Hayden, Suresh C Tyagi. "A" is for Amylin and Amyloid in type 2 Diabetes melitus. JOP.J Panreas)Online 2001; 2(4):124-139.
http://www.joplink.net/prev/200107/200107_02.pdf

9. Nauck M.A. Homberger E.,Siegel E.G., Allen R.C. Eaton R.P. Ebert R.,Creutzfeidt W Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J. Clin Endocrinol Metab. 1986;63:492-496.

10. Nauck M.A.,Klein N.,Orskov C., Holst J.J, Willms B.,Creutzfeldt W Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36 amide) in type 2 (non-insulin dependent) diabetic patients. Diabetologia. 1993;36:741-744.

11. Roger D. Reidelberger, Urban Arnelo, Lars Granqvist, and Johan Permert Comparative effects of amylin and cholecystokinin on food intake and gastric emptying in rats Am J Physiol Regul Integr Comp Physiol, Vol. 280, Issue 3, R605-R611, March 2001

12. Xiaoyin Wu, Jun Gao, Jin Yan, Chung Owyang and Ying Li Hypothalamus-Brain Stem Circuitry Responsible for Vagal Efferent Signaling to the Pancreas Evoked By Hypoglycemia in Rat Journal of Neurophysiol 91: 1734-1747, 2004.


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