Diabetes Mellitus - A Detailed Overview PDF

Mehmet Köroğlu MD. Internal Medicine igugelisim gelisimedu Diabetes mellitus is taken from the Greek word diabetes, meaning siphon - to pass through and the Latin word mellitus meaning sweet The most obvious sign of diabetes is excessive urination. Water passes through the body...

Mehmet Köroğlu MD. Internal Medicine igugelisim gelisimedu Diabetes mellitus is taken from the Greek word diabetes, meaning siphon - to pass through and the Latin word mellitus meaning sweet The most obvious sign of diabetes is excessive urination. Water passes through the body of a person with diabetes as if it were being siphoned from the mouth through the urinary system and out of the body. Water passes through the body of a person with diabetes as if it were being siphoned from the mouth through the urinary system and out of the body. Mellitus comes from a Latin word that means sweet like honey. The urine of a person with diabetes contains extra sugar (glucose). Ancient Chinese and Japanese physicians noticed dogs were particularly drawn to some people’s urine. When the urine was examined they found the urine had a sweet taste. What made the urine sweet were high levels of glucose, or sugar.That is how this discovery of sweet urine became part of the name, diabetes mellitus. In 1679,the physician Thomas Willis, tasted the urine of a person with diabetes and described as ‘wonderfully sweet’ like honey Do not confuse when you see the term ‘ Diabetes Insipidus’. İnsipidus is the urine is tasteless, whereas mellitus suggests it is sweet from its sugar content. This terminology dates back to a time when physicians literally dipped a finger in the patient's urine and tested its taste. Diabetes insipidus another disease that is from kidney origin. A review of the history shows that the term "diabetes" was first used by Apollonius of Memphis around 250 to 300 BC. Ancient Greek, Indian, and Egyptian civilizations discovered the sweet nature of urine in this condition, and hence the propagation of the word Diabetes Mellitus came into being. Mering and Minkowski, in 1889, discovered the role of the pancreas in the pathogenesis of diabetes. In 1922 Banting, Best, and Collip purified the hormone insulin from the pancreas of cows at the University of Toronto, leading to the availability of an effective treatment for diabetes in 1922. Over the years, exceptional work has taken place, and multiple discoveries, as well as management strategies, have been created to tackle this growing problem. Unfortunately, even today, diabetes is one of the most common chronic diseases in the country and worldwide. In the US, it remains as the seventh leading cause of death. Diabetes has been around for centuries. In fact, cases of diabetes can be traced as far back as the ancient Egyptians. In the 1800s, dogs helped scientist study and determine how the pancreas and lack of the hormone insulin revealed signs of diabetes. In the 1930s up through the 1970s, society commonly referred to individuals with diabetes as having “sugar,” but the correct medical term for diabetes is ‘diabetes mellitus’. Today, healthcare teams most commonly refer to it as ‘diabetes’. History of the treatment of diabetes Sushruta, Arataeus, and Thomas Willis were the early pioneers of the treatment of diabetes. Greek physicians prescribed exercise - preferably on horseback to alleviate excess urination. Some other forms of therapy applied to diabetes include wine, overfeeding to compensate for loss of fluid weight, starvation diet, etc. In 1776, Matthew Dobson confirmed that the sweet taste of urine of diabetics was due to excess of a kind of sugar in the urine and blood of people with diabetes. In ancient times and medieval ages diabetes was usually a death sentence. Aretaeus did attempt to treat it but could not give a good outcome. Sushruta (6th century BCE) an Indian healer identified diabetes and classified it as “Madhumeha”. Here the word “madhu” means honey and combined the term means sweet urine. The ancient Indians tested for diabetes by looking at whether ants were attracted to a person's urine. The Korean, Chinese, and Japanese words for diabetes are based on the same ideographs which mean “sugar urine disease”. In Persia Avicenna (980–1037) provided a detailed account on diabetes mellitus in “'The Canon of Medicine”. He described abnormal appetite and the decline of sexual functions along with sweet urine. He also identified diabetic gangrene. Avicenna was the first to describe diabetes insipidus very precisely. It was much later in the 18th and 19th century that Johann Peter Frank (1745–1821) differentiated between diabetes mellitus and diabetes insipidus Joseph von Mering and Oskar Minkowski in 1889 discovered the role of pancreas in diabetes. They found that dogs whose pancreas was removed developed all the signs and symptoms of diabetes and died shortly afterwards. In 1910, Sir Edward Albert Sharpey-Schafer found that diabetes resulted from lack of insulin. He termed the chemical regulating blood sugar as insulin from the Latin “insula”, meaning island, in reference to the insulin-producing islets of Langerhans in the pancreas. In 1921 Sir Frederick Grant Banting and Charles Herbert Best repeated the work of Von Mering and Minkowski and went ahead to demonstrate that they could reverse induced diabetes in dogs by giving them an extract from the pancreatic islets of Langerhans of healthy dogs. Banting, Best, and their chemist colleague Collip purified the hormone insulin from pancreases of cows at the University of Toronto. This led to the availability of an effective treatment for diabetes in 1922. For this, Banting and laboratory director MacLeod received the Nobel Prize in Physiology or Medicine in 1923; both shared their Prize money with others in the team who were not recognized, in particular Best and Collip. Banting and Best made the patent available free of charge so that millions of diabetics worldwide could get access to insulin. In 1922 January, Leonard Thompson, 14, a charity patient at the Toronto General Hospital, became the first person to receive and injection of insulin to treat diabetes. Thompson lived another 13 years before dying of pneumonia at age 27. Diabetes is a condition that results from lack of the hormone insulin in a person's blood, or when the body has a problem using the insulin it produces (insulin resistance). Diabetes mellitus is a group of metabolic disorders characterized by elevated levels of blood glucose(hyperglycemia) resulting from defects in insulin production & secretion, decreased cellular response to insulin or both.  Can be diagnosed by demonstrating any one of the following:  Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)  Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a 75 g oral glucose load as in a glucose tolerance test.  Symptoms of high blood sugar and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)  Glycated hemoglobin (HbA1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %) The pancreas is a long, slender organ, most of which is located posterior to the bottom half of the stomach. The pancreas has an endocrine function. Its pancreatic islets—clusters of cells formerly known as the islets of Langerhans— secrete the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide (PP). Pancreas is an elongated organ with one end broad (shaped like a hook) & the other end narrowing to a tail. This organ lies sideways, the hook on the right side and turned downwards. It lies behind & below the stomach fitted in the C-shaped concavity of the loop of duodenum (small intestine)  Smaller part consists of isolated islands of endocrine tissues called as ISLETS OF LANGERHANS dispersed throughout. It forms only 1% of the total pancreatic mass. 1-2 million in number 0.3 mm in diameter These secrete  B or Beta cells (60%) A or Alpha cells (25%) secrete Insulin and secrete Glucagon Amylin Islets of Langerhans F or PP cells are very D or Delta cells (10%) few and secrete secrete Somatostatin Pancreatic Polypeptide  It is a Peptide hormone. It consists of 2 amino acid (51AA) chains that are joined together by disulphide linkages. If the 2 AA chains are split apart then the functional activity of insulin is lost. It has a molecular weight of 5808 da  Synthesis of Insulin occurs in the rough endoplasmic reticulum of β- cells in Islets of Langerhans.  It is initially produced as a Preprohormone called Preproinsulin (mw: 11,500) which is cleaved in the ER to yield Proinsulin (mw: 9,000).  Proinsulin is further cleaved in Golgi apparatus to yield Insulin and its peptide fragment which is also called the C-peptide (connecting peptide).  C-peptide is a connecting peptide that connects α and β chains.  These both are then packaged in secretory vesicles & released when the stimulus arrives.  Plasma half-life: 6 minutes  Cleared from the circulation in 10-15 minutes It is a tetramer formed by 4 glycoprotein subunits: 2 alpha subunits (present outside the cell membrane) 2 beta subunits (penetrate through the memb. Into the cell cytoplasm) The alpha and beta subunits are linked by disulfide bonds. It is an enzyme-linked receptor. Contains multiple enzyme groups called as Insulin-receptor substrates (IRS). Different types of IRS are expressed in different tissues (IRS1-3).  Insulin attaches to alpha subunit of receptor ↓ The beta subunit of the receptor becomes autophosphorylated ↓ Tyrosine kinase is activated ↓ IRS is Phosphorylated. ↓ Action exerted e.g. glucose uptake by the cells is enhanced.  Insulin is an ANABOLIC hormone.  Insulin is the hormone of the FED/ ABSORPTIVE state.  Insulin has important effects on: - CHO - Fats - Proteins  It LOWERS blood glucose levels of: - Glucose - fatty acids - amino acids  It is a hormone associated with ENERGY ABUNDANCE.  Brain uses ONLY Glucose as its energy source, therefore, it is important that blood glucose levels be maintained above a critical level.  Brain is PEREMEABLE to Glucose & can use it even without the intermediation of Insulin.  When blood glucose levels fall too low ( 20- 50mg/ 100ml), symptoms of hypoglycemic shock develop.  Hypoglycemic shock is characterized by progressive nervous irritability that leads to fainting, seizures & even coma Role of GLUT: The transport of glucose b/w blood and different tissue cells is accomplished by the proteins called GLUCOSE TRANSPORTERS (GLUT).  Fourteen different Glucose transporters have been characterized, GLUT 1-14 in the order of discovery.  The GLUT all accomplish passive diffusion of Glucose across the cell membrane. Once inside the cell, the Glucose is immediately phosphorylated to Glucose-6-Phosphate which cannot leave the cell through the bi-directional GLUT protein and is “trapped” inside the cell. .  Each GLUT has been evolved for a different task & a different tissue.  GLUT 1,2,3 & 5 are NOT affected by insulin: - GLUT-1: transports glucose across blood brain barrier - GLUT-2: from kidney & intestinal cells into the blood stream. Glucose enters the kidney & intestinal cells by SGLT (Na & Glu cotransporters) - GLUT-3: neurons - GLUT-4: in all major cells using Glucose (as muscle and adipose tissues) Therefore, in all these tissues the glucose entry is insulin independent   Only GLUT-4 is insulin-dependant & occurs in the muscles & adipocytes.  These cells maintain a pool of GLUT-4 molecules in vesicles in their cell cytoplasm.  Insulin attaches to the receptor ↓ Insulin receptor is activated ↓ Vesicles containing GLUT-4 move rapidly to the cell membrane ↓ Vesicles fuse with the cell membrane, inserting the transporter in the membrane ↓ When insulin action ceases, the transporter-containing patches of membrane are endocytosed ↓ Vesicles are reformed ready for the next action 1. Insulin stimulates Glucose uptake by the cells (mostly thru GLUT-4). 2. Insulin stimulates Glycogenesis in both the Liver & the Skeletal muscles. 3. It inhibits Glycogenolysis. 4. It inhibits Gluconeogenesis. 5. It promotes liver uptake, use & storage of Glucose Throughout the day, the Under resting conditions, muscles use Fatty the cells are Acids as an energy dependant on GLUT-4 source EXCEPT: for glucose uptake But, - During moderate With moderate or severe & heavy exercise exercise, special GLUT- when they uptake 4 vesicles (present Glucose through only in muscles) move Insulin-independent into cell membrane in pathway. response to exercise - POST-MEAL: Insulin only & do not require Insulin facilitates large ↓ amounts of glucose into the cells. That is why EXERCISE LOWERS BLOOD SUGAR! Major action of GH on CHO metabolism is the conservation of Glucose:  GH has effect opposite to the effects of insulin, thus also called insulin-antagonistic effects. However, GH is also Insulinogenic in nature (stimulates Insulin secretion).  Diabetes control deteriorates when GH is infused in patients with Type I Diabetes.  Hypoglycemia is a potent stimulus for GH release.  GH in pharmacological doses can induce a Diabetic state in animals.  Insulin enhances uptake of many amino acid by the cells (esp. valine, leucine, tyrocine). It is interesting to note that Insulin causes uptake of app. 6 amino acids while GH stilmulates the uptake of another 6 AA, thus both target different AA. So, they are synergistic in action.  It increases the transcription of DNA (more RNA formed).  It increases the translation of mRNA on the ribosomes forming new proteins.  Insulin inhibits protein catabolism & decreases the rate of AA release from the cells.  In the liver, it decreases the rate of gluconeogenesis & thus conserves amino acids for protein synthesis.  Insulin promotes protein synthesis & inhibits its Catabolism.  It is thus essential for growth.  Insulin & Growth hormone thus act synergistically to promote growth.  INSULIN PROMOTES 1. Synthesis of Fatty acids and Triglycerides 2. Transport of Fatty acids into the adipose tissues. 3. Storage of Fat in the adipose tissue.  Insulin PROMOTES uptake of Glucose & amino acids by different cells of the body. In doing so it lowers the blood glucose levels post meal.  Insulin increases Glycogenesis, Lipogenesis & protein formation.  Insulin inhibits Glycolysis, Gluconeogensis, Lipolysis & protein breakdown.  It promotes growth.  Several tissues do not depend on insulin for their glucose uptake—namely: the brain, working muscles, and liver.