Diabetes mellitus is characterized by abnormally high levels of sugar (glucose) in the blood. pregnancy, and other forms of diabetes are very rare and are …
Diabetes
Introduction to Diabetes
1 Introduction to Diabetes
Created: July 7, 2004
Diabetes mellitus is characterized by abnormally high levels of sugar glucose in the blood When the amount of glucose in the blood increases, eg, after a meal, it triggers the release of the hormone insulin from the pancreas Insulin stimulates muscle and fat cells to remove glucose from the blood and stimulates the liver to metabolize glucose, causing the blood sugar level to decrease to normal levels [http://wwwncbinlmnihgov:80/books/bvfcgi?callbvView ShowSectionridmcbfiggrp5903] In people with diabetes, blood sugar levels remain high This may be because insulin is not being produced at all, is not made at sufficient levels, or is not as effective as it should be The most common forms of diabetes are type 1 diabetes 5, which is an autoimmune disorder, and type 2 diabetes 95, which is associated with obesity Gestational diabetes is a form of diabetes that occurs in pregnancy, and other forms of diabetes are very rare and are caused by a single gene mutation For many years, scientists have been searching for clues in our genetic makeup that may explain why some people are more likely to get
diabetes than others are The Genetic Landscape of Diabetes introduces some of the genes that have been suggested to play a role in the development of diabetes
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Introduction to Diabetes
Classification
Diabetes is classified by underlying cause The categories are: type 1 diabetes–an autoimmune disease in which the bodys own immune system attacks the pancreas [http://wwwncbinlmnih gov:80/books/bvfcgi?toolbookshelfcallbvViewShowSectionridimmfiggrp1942], rendering it unable to produce insulin; type 2 diabetes–in which a resistance to the effects of insulin or a defect in insulin secretion may be seen; gestational diabetes; and other types Table 1 compares the presentation phenotype of type 1 and type 2 diabetes Table 1 Comparison of Type 1 and Type 2 Diabetes
Type 1 diabetes Phenotype Onset primarily in childhood and adolescence Often thin or normal weight Prone to ketoacidosis Insulin administration required for survival Pancreas is damaged by an autoimmune attack Absolute insulin deficiency Treatment: insulin injections Type 2 diabetes Onset predominantly after 40 years of age Often obese No ketoacidosis Insulin administration not required for survival Pancreas is
not damaged by an autoimmune attack Relative insulin deficiency and/or insulin resistance Treatment: 1 healthy diet and increased exercise; 2 hypoglycemic tablets; 3 insulin injections Increased prevalence in relatives Identical twin studies: usually above 70 concordance HLA association: No
Genotype
Increased prevalence in relatives Identical twin studies: 50 concordance HLA association: Yes
Type 2 diabetes is increasingly diagnosed in younger patients
Type 2 diabetes commonly occurs in adults who are obese There are many underlying factors that contribute to the high blood glucose levels in these individuals An important factor is the bodys resistance to insulin in the body, essentially ignoring its insulin secretions A second factor is the falling production of insulin by the beta cells of the pancreas Therefore, an individual with type 2 diabetes may have a combination of deficient secretion and deficient action of insulin In contrast to type 2, type 1 diabetes most commonly occurs in children and is a result of the bodys immune system attacking and destroying the beta cells The trigger for this autoimmune attack is not clear, but the result is the end of insulin
production
References
1 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Report of the expert committee on the diagnosis and classification of diabetes mellitus Diabetes Care 26:S5-S20; 2003 PubMed
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Introduction to Diabetes
History of Diabetes
Physicians have observed the effects of diabetes for thousands of years For much of this time, little was known about this fatal disease that caused wasting away of the body, extreme thirst, and frequent urination It wasnt until 1922 that the first patient was successfully treated with insulin One of the effects of diabetes is the presence of glucose in the urine glucosuria Ancient Hindu writings, many thousands of years old, document how black ants and flies were attracted to the urine of diabetics The Indian physician Sushruta in 400 BC described the sweet taste of urine from affected individuals, and for many centuries to come, the sweet taste of urine was key to diagnosis Around 250 BC, the name diabetes was first used It is a Greek word that means to syphon, reflecting how diabetes seemed to rapidly drain fluid from the affected individual The Greek physician Aretaeus noted that as affected
individuals wasted away, they passed increasing amounts of urine as if there was liquefaction of flesh and bones into urine The complete term diabetes mellitus was coined in 1674 by Thomas Willis, personal physician to King Charles II Mellitus is Latin for honey, which is how Willis described the urine of diabetics as if imbued with honey and sugar Up until the mid-1800s, the treatments offered for diabetes varied tremendously Various fad diets were prescribed, and the use of opium was suggested, as were bleeding and other therapies The most successful treatments were starvation diets in which calorie intake was severely restricted Naturally, this was intolerable for the patient and at best extended life expectancy for a few years A breakthrough in the puzzle of diabetes came in 1889 German physicians Joseph von Mering and Oskar Minkowski surgically removed the pancreas from dogs The dogs immediately developed diabetes Now that a link was established between the pancreas gland and diabetes, research focused on isolating the pancreatic extract that could treat diabetes When Dr Frederick Banting took up the challenge of isolating a pancreatic extract, he was met with much skepticism
Many great physiologists had tried and failed to isolate an internal secretion from the pancreas But Banting, a surgeon, persisted and in May 1921, he began work in the laboratory of Professor John Macloed in Toronto, Canada Charles Best, a medical student at the time, worked as his assistant To concentrate what we now know as insulin, Banting tied the pancreatic ducts of dogs The pancreatic cells that released digestive enzymes and could also destroy insulin degenerated, but the cells that secreted insulin were spared Over several weeks the pancreas degenerated into a residue from which insulin could be extracted In July 1921, a dog that had had its pancreas surgically removed was injected with an extract collected from a duct-tied dog In the two hours that followed the injection, the blood sugar level of the dog fell, and its condition improved Another de-pancreatized diabetic-like dog was kept alive for eight days by regular injections until supplies of the extract, at that time called isletin, were exhausted Further experiments on dogs showed that extracts from the pancreas caused a drop in blood sugar, caused glucose in the urine to disappear, and produced a marked improvement
in clinical condition So long as the extract was being given, the dogs were kept alive The supply of the 1-3
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Introduction to Diabetes extract was improved: the pancreas of different animals were used until that of the cow was settled upon This extract kept a de-pancreatized dog alive for 70 days Dr J Collip, a biochemist, was drafted to continue improving the purity of the pancreas extract, and later, Best carried on this work A young boy, Leonard Thompson, was the first patient to receive insulin treatment On January 11, 1922, aged 14 and weighing only 64 pounds, he was extremely ill The first injections of insulin only produced a slight lowering of blood sugar level The extract still was not pure enough, and abscesses developed at the injection site Collip continued to refine the extract Several weeks later, Leonard was treated again and showed a remarkable recovery His blood sugar levels fell, he gained weight and lived for another 13 years He died from pneumonia at the age of 27 During the spring of 1922, Best increased the production of insulin to enable the treatment of diabetic patients coming to the Toronto clinic Over the next 60 years, insulin was further
refined and purified, and long-acting and intermediate types were developed to provide more flexibility A revolution came with the production of recombinant human DNA insulin in 1978 Instead of collecting insulin from animals, new human insulin could be synthesized In 1923, Banting and Macloed were awarded the Nobel Prize for the discovery of insulin Banting split his prize with Best, and Macloed split his prize with Collip In his Nobel Lecture, Banting concluded the following about their discovery: Insulin is not a cure for diabetes; it is a treatment It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life
Link Roundup
Discovery of Insulin
Nobel Prize [wwwnobelse/medicine/laureates/1923/indexhtml] for the discovery of insulin Development of Insulin [http://digitallibraryutorontoca/insulin/], University of Toronto Banting Digital library [http://wwwnewtecumsethlibraryonca/banting/], New Tecumseth Public Library, Canada Discovery of insulin [wwwdiscoveryofinsulincom/Homehtm]
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Introduction to Diabetes
Epidemiology
Over 18 million Americans
have diabetes; of these, about 5 million do not know they have the disease 1 Type 1 diabetes accounts for 5-10 of cases, affecting 1 of 400 children and adolescents Type 2 diabetes is extremely common, accounting for 90-95 of all cases of diabetes This form of diabetes can go undiagnosed for many years, but the number of cases that are being diagnosed is rising rapidly, leading to reports of a diabetes epidemic
The Type 2 Diabetes Epidemic
When people think of epidemics, they often think of infectious diseases such as SARS, HIV, or the flu However, the prevalence of type 2 diabetes is now at epidemic proportions In the United States, diabetes accounts for over 130 billion dollars of health care costs and is the fifth leading cause of death 2 The number of new cases being diagnosed continues to rise It has been estimated that of the children born in the year 2000, 1 of 3 will suffer from diabetes at some point in their lifetime 3 Diabetes is predicted to become one of the most common diseases in the world within a couple of decades, affecting at least half a billion people 4
Estimate your risk of developing Type 2 Diabetes [wwwhealthcalculatorsorg/calculators/diabetesasp]
In the
past, type 2 was rarely seen in the young, hence its original name of adult-onset diabetes But now type 2 diabetes is increasingly being diagnosed in young adults and even in children In Japan, more children suffer from type 2 than type 1 juvenile onset diabetes This young generation of diabetics will have many decades in which to develop the complications of diabetes In 1990, 49 of the American population were diagnosed with diabetes see Flash Animation 1 This increased to 79 by the year 2001 5
Obesity
The driving force behind the high prevalence of diabetes is the rise of obesity [http://wwwncbi nlmnihgov:80/books/bvfcgi?callbvViewShowTOCridobesityTOC] in the population In todays society, it can be difficult to maintain a healthy weight We have the combination of ample food and a sedentary lifestyle This is in stark contrast to only a couple of hundred years ago, when people were more active and food supplies were not as abundant As a result, many of us are heavier than we should be
Calculate your ideal weight [wwwdrkoopcom/templateasp?pageibwap93]
Being overweight or obese is defined by a calculation called the Body Mass Index BMI It is a calculation that takes your height and
weight into consideration and gives you a score A score of 18249 is a healthy weight If you are overweight, your score lies within the range to 25299; a score of 30 and above indicates obesity 1-5
Diabetes
Calculate your BMI [http://nhlbisupportcom/bmi/bmicalchtm]
Introduction to Diabetes
In 1991, it was estimated that 12 of the population were obese 5 By the year 2001, this had increased to an estimated 209 of the population; this represents over 44 million obese adult Americans A more recent study estimated that a record 30 of the American population are now obese 6 see Flash Animation 2 Obesity is a major problem for the United states Every year, an estimated 300,000 US adults die of causes related to obesity 7 Obesity is also a huge economic burden, accounting for up to 4 of healthcare costs in the United States 8
Thrifty Genes
Epidemics of infectious diseases increase when there is increased spread of the infectious agent and decrease when the number of victims who are susceptible falls they either become immune or they die An epidemic of a genetic disease such as type 2 diabetes is similar The number of cases rises when there is a rise in environmental risk abundant food
supplies, lack of activity and decreases when the number of susceptible individuals falls by deaths from the complications of diabetes The classic example of an epidemic of diabetes is found on an remote island in the Pacific Ocean, the island of Nauru Before the turn of the 20th century, the lifestyle of Nauruans was harsh The soil was poor, agriculture was difficult, and frequent episodes of starvation were common Despite these adverse conditions, the islanders were noted to be heavy In 1922, it was discovered that Nauru contained phosphate rock, which was then mined for use in fertilizer, and for which the islanders received royalties Over several decades, the Nauruans became extremely wealthy, and with their new-found riches came major lifestyle changes Food was now abundant and could be bought from stores Instead of fishing and farming, Nauruans now led sedentary lives By the 1950s, type 2 diabetes exploded from being non-existent in this population to affecting 2 of 3 adults over the age of 55 and becoming a common cause of death The case of the Nauruans is an extreme case of how type 2 diabetes can rapidly reach epidemic proportions, and thrifty genes may be involved It has
been postulated by Neel 9 that genes that are metabolically thrifty give a survival advantage in times when there is a constant threat of famine and starvation When food is abundant, these genes aid the efficient metabolism of the food, enabling rapid build up of fat stores This enabled people like the Nauruans to survive food shortages later on But when food is always abundant, a thrifty genetic makeup turns into a survival disadvantage Thrifty genes cause obesity, which in turn predisposes to diabetes The epidemic that took hold of the island of Nauru is now emerging in developing countries and already has a firm hold on the developed world
References
1 National Diabetes Statistics fact sheet: general information and national estimates on diabetes in the United States National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health US Department of Health and Human Services
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2 Hogan P, Dall T, Nikolov P Economic costs of diabetes in the US in 2002 Diabetes Care 263:917932; 2003 PubMed 3 Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF Lifetime risk for diabetes mellitus in the United States JAMA
29014:18841890; 2003 PubMed 4 King H, Aubert RE, Herman WH Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections Diabetes Care 219:14141431; 1998 PubMed 5 Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 JAMA 2891:7679; 2001 PubMed 6 Flegal KM, Carroll MD, Ogden CL, Johnson CL Prevalence and trends in obesity among US adults, 1999-2000 JAMA 28814:17231727; 2002 PubMed 7 Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB Annual deaths attributable to obesity in the United States JAMA 28216:15301538; 1999 PubMed 8 Allison DB, Zannolli R, Narayan KM The direct health care costs of obesity in the United States Am J Public Health 898:11941199; 1999 PubMed 9 Neel JV Diabetes mellitus: a thrifty genotype rendered detrimental by progress? JAMA 14:353362; 1962 PubMed
Box 1: Increase of diabetes in adults in the United States
References
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 JAMA 2891:7679; 2001 PubMed To view this you will need to have
Flash [http://wwwmacromediacom/go/getflashplayer] installed on your computer
Box 2: Rise of obesity in the United States
References
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001 JAMA 2891:7679; 2001 PubMed To view this you will need to have Flash [http://wwwmacromediacom/go/getflashplayer] installed on your computer
Link Roundup
Calculators
Diabetes Type 2 Risk Calculator [wwwhealthcalculatorsorg/calculators/diabetesasp], University of Maryland Medical Center Calculate your ideal weight [wwwdrkoopcom/templateasp?pageibwap93], according to Dr Koop Calculate your BMI [nhlbisupportcom/bmi/bmicalchtm] at the National Heart, Lung, and Blood Institute
Healthy Living
The DASH diet [wwwnhlbinihgov/health/public/heart/hbp/dash/], National Heart, Lung, and Blood Institute Advice from the Obesity Education Initiative [wwwnhlbinihgov/about/oei/indexhtm], National Heart, Lung, and Blood Institute The Presidents challenge [wwwpresidentschallengeorg/] Advice from the Surgeon General [wwwsurgeongeneralgov/topics/obesity/calltoaction/fact_whatcanyoudohtm]
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Introduction to
Diabetes
Physiology and Biochemistry of Sugar Regulation
Overview of Glucose Metabolism
Glucose is an essential fuel for the body Figure 1The amount of glucose in the bloodstream is regulated by many hormones, the most important being insulin Insulin is the hormone of plenty–it is released when glucose is abundant and stimulates the following:
muscle and fat cells to remove glucose from the blood cells to breakdown glucose, releasing its energy in the form of ATP via glycolysis and the
citric acid cycle
the liver and muscle to store glucose as glycogen short-term energy reserve adipose tissue to store glucose as fat long-term energy reserve cells to use glucose in protein synthesis
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Figure 1: Overview of glucose metabolism Glucose is used for many purposes in the body It can be converted into energy via pyruvate and the tricarboxylic acid TCA cycle, as well as being converted to fat long-term storage and glycogen short-term storage Some amino acids may also be synthesized directly from pyruvate; thus, glucose may also indirectly contribute to protein synthesis
Glucagon is the main hormone opposing the action
[http://wwwncbinlmnihgov:80/books/bv fcgi?toolbookshelfcallbvViewShowSectionridmcbfiggrp5903] of insulin and is released when food is scarce Whereas insulin triggers the formation of glycogen an energy-requiring process, or an anabolic effect, glucagon triggers glycogen breakdown, which releases energy a catabolic effect Glucagon also helps the body to switch to using resources other than glucose, such as fat and protein Figure 2
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Figure 2: Anabolism and catabolism of glucose Glucose metabolism involves both energy-producing catabolic, shown in orange and energy-consuming anabolic, shown in green processes
Regulation of Blood Glucose
Blood glucose levels are not constant–they rise and fall depending on the bodys needs, regulated by hormones This results in glucose levels normally ranging from 70 to 110 mg/dl The blood glucose level can rise for three reasons: diet, breakdown of glycogen, or through hepatic synthesis of glucose Eating produces a rise in blood glucose, the extent of which depends on a number of factors such as the amount and the type of carbohydrate eaten ie, the glycemic index, the rate of digestion, and the rate of
absorption Because glucose is a polar molecule, its absorption across the hydrophobic gut wall requires specialized glucose transporters GLUTS [http://wwwncbinlm nihgov:80/books/bvfcgi?callbvViewShowSectionridendocrinbox54] of which there are five types In the gut, GLUT2 and GLUT5 [http://wwwncbinlmnihgov:80/books/bvfcgi?callbv ViewShowSectionridendocrinbox53] are the most common The liver is a major producer of glucose–it releases glucose from the breakdown of glycogen and also makes glucose from intermediates of carbohydrate, prote 
in, and fat metabolism The liver is also a major consumer of glucose and can buffer glucose levels see Box 1 It receives glucose-rich blood directly from the digestive tract via the portal vein Figure 3 The liver quickly removes large amounts of glucose from the circulation so that even after a meal, the blood glucose levels rarely rise above 110 mg/dl in a non-diabetic
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Figure 3: The portal circulation The portal vein drains almost all of the blood from the digestive tract and empties directly into the liver This circulation of nutrient-rich blood between the gut and liver is called the portal circulation It
enables the liver to remove any harmful substances that may have been digested before the blood enters the main blood circulation around the body–the systemic circulation
After a Meal–the Role of Insulin
The rise in blood glucose following a meal is detected by the pancreatic beta cells, which respond by releasing insulin Insulin increases the uptake and use of glucose by tissues such as skeletal muscle and fat cells This rise in glucose also inhibits the release of glucagon, inhibiting the production of glucose from other sources, eg, glycogen break down Figure 4
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Figure 4: Changes in key hormones after a meal Changes in blood levels of glucose, insulin, and glucagon after a carbohyrate-rich meal ingested at time 0 minutes
1 Use Glucose
Once inside the cell, some of the glucose is used immediately via glycolysis This is a central pathway of carbohydrate metabolism because it occurs in all cells in the body, and because all sugars can be converted into glucose and enter this pathway During the well-fed state, the high levels of insulin and low levels of glucagon stimulate glycolysis, which releases energy and produces carbohydrate
intermediates that can be used in other metabolic pathways
Glycolysis [http://wwwncbinlmnihgov:80/books/bvfcgi?callbvViewShowSectionridstryersection2206] in Stryers Biochemistry
2 Make Glycogen
Any glucose that is not used immediately is taken up by the liver and muscle where it can be converted into glycogen [http://wwwncbinlmnihgov:80/books/bvfcgi?callbvView ShowSectionridstryerchapter2911] glycogenesis Insulin stimulates glycogenesis in the liver by:
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stimulating hepatic glycogen synthetase the enzyme that catalyzes glycogen synthesis in
the liver
inhibiting hepatic glycogen phosphorylase the enzyme that catalyzes glycogen breakdown
in the liver
inhibiting glucose synthesis from other sources inhibits gluconeogenesis
Insulin also encourages glycogen formation in muscle, but by a different method Here it increases the number of glucose transporters GLUT4 on the cell surface This leads to a rapid uptake of glucose that is converted into muscle glycogen
Glycogen metabolism [http://wwwncbinlmnihgov:80/books/bvfcgi?callbvViewShowSectionridstryer chapter2911] in Stryers Biochemistry
3 Make Fat
When glycogen stores are fully replenished,
excess glucose is converted into fat in a process called lipogenesis Glucose is converted into fatty acids that are stored as triglycerides three fatty acid molecules attached to one glycerol molecule for storage Insulin promotes lipogenesis by:
increasing the number of glucose transporters GLUT4 expressed on the surface of the fat
cell, causing a rapid uptake of glucose
increasing lipoprotein lipase activity, which frees up more fatty acids for triglyceride synthesis In addition to promoting fat synthesis, insulin also inhibits fat breakdown [http://wwwncbinlmnih gov:80/books/bvfcgi?callbvViewShowSectionridstryerchapter3038] by inhibiting hormonesensitive lipase an enzyme that breaks down fat stores As a result, there are lower levels of fatty acids in the blood stream
Fatty acid metabolism [http://wwwncbinlmnihgov:80/books/bvfcgi?callbvViewShowSectionridstryer chapter3038] in Stryers Biochemistry
Insulin also has an anabolic effect on protein metabolism It stimulates the entry of amino acids into cells and stimulates protein production from amino acids
Fasting–the Role of Glucagon
Fasting is defined as more than eight hours without food The resulting fall in blood sugar
levels inhibits insulin secretion and stimulates glucagon release Glucagon opposes many actions of insulin Most importantly, glucagon raises blood sugar levels by stimulating the mobilization of glycogen stores in the liver, providing a rapid burst of glucose In 1018 hours, the glycogen
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Introduction to Diabetes stores are depleted, and if fasting continues, glucagon continues to stimulate glucose production by favoring the hepatic uptake of amino acids, the carbon skeletons of which are used to make glucose In addition to low blood glucose levels, many other stimuli stimulate glucagon release including eating a protein-rich meal the presence of amino acids in the stomach stimulates the release of both insulin and glucagon, glucagon prevents hypoglycemia that could result from unopposed insulin and stress the body anticipates an increased glucose demand in times of stress
Starvation
The metabolic state of starvation in the USA is more commonly found in people trying to lose weight rapidly or in those who are too unwell to eat After a couple of days without food, the liver will have exhausted its stores of glycogen but continues to make glucose from protein amino
acids and fat glycerol The metabolism of fatty acids from adipose tissue is a major source of energy for organs such as the liver Fatty acids are broken down to acetyl-CoA, which is channeled into the citric acid cycle and generates ATP As starvation continues, the levels of acetyl-CoA increase until the oxidative capacity of the citric acid cycle is exceeded The liver processes these excess fatty acids into ketone bodies 3-hydroxybutyrate to be used by many tissues as an energy source The most important organ that relies on ketone production is the brain because it is unable to metabolize fatty acids During the first few days of starvation, the brain uses glucose as a fuel If starvation continues for more than two weeks, the level of circulating ketone bodies is high enough to be used by the brain This slows down the need for glucose production from amino acid skeletons, thus slowing down the loss of essential proteins
Starvation in the Midst of Plenty
Diabetes is often referred to as starvation in the midst of plenty because the intracellular levels of glucose are low, although the extracellular levels may be extremely high As in starvation, type 1 diabetics use non-glucose
sources of energy, such as fatty acids and ketone bodies, in their peripheral tissues But in contrast to the starvation state, the production of ketone bodies can spiral out of control Because the ketones are weak acids, they acidify the blood The result is the metabolic state of diabetic ketoacidosis DKA Hyperglycemia and ketoacidosis are the hallmark of type 1 diabetes Figure 5 Hypertriglyceridemia is also seen in DKA The liver combines triglycerol with protein to form very low density lipoprotein VLDL It then releases VLDL into the blood In diabetics, the enzyme that normally degrades lipoproteins lipoprotein lipase is inhibited by the low level of insulin and the high level of glucagon As a result, the levels of VLDL and chylomicrons made from lipid from the diet are high in DKA
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Figure 5: Metabolic changes in diabetic ketoacidosis Hyperglycemia is caused by the increased production of glucose by the liver driven by glucagon and the decreased use of glucose of insulin by peripheral tissues because of the lack of insulin
Low-Carbohydrate Diet
Low-carbohydrate diets, such as the Atkins and South Beach diets, are currently popular ways to
lose weight Such diet plans involve restricting the type and amount of carbohydrate eaten One of the earliest descriptions of a low-carbohydrate diet was by William Banting in the 1860s in England At the age of 66, Banting found success in following a carbohydrate-restricted diet: in the course of one year, he lost 46 pounds of his initial weight of 202 pounds His impression was that any starchy or saccharine matter tends to the disease of corpulence in advanced life He claimed he was never hungry and that the great charms and comfort of the system are that its effects are palpable within a week of trial and creates a natural stimulus to persevere for a few weeks more In a recent small trial, 63 obese men and women were assigned to either a low-carbohydrate diet or a low-fat diet 1 People on both diets lost weight The carbohydrate-restricted group initially lost weight at a faster rate, but when reviewed at the end of the year there was no significant difference in weight loss between the two groups 1 It was found that low-carbohydrate dieters who were allowed unrestricted amounts of protein and fat actually had a lower energy intake than the low-fat diets who were limited in their
calorie intake It may be that when carbohydrates are restricted, weight loss is due to a lower calorie intake due to the monotony of the diet It is also possible that the lower calorie intake may be because of a change in peripheral or central saiety signals, leaving people feeling more full after a meal A second study compared the effects of a carbohydrate-restricted diet on the risk of developing atherosclerosis 2 132 severely obese men and women were assigned to either a lowcarbohydrate or low-fat diet Again, after a 6-month period both groups lost weight They became 1-15
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Introduction to Diabetes more sensitive to insulin, and their triglyceride TG levels, a type of fat that is a risk factor for atherosclerosis, improved However, the carbohydrate-restricted group lost more weight and showed a greater improvement in insulin sensitivity and TG levels After one year, the weight loss between the two groups was similar, but the cardiogenic risk factors were improved in the lowcarbohydrate dieters, TG levels were lower, and levels of HDL cholesterol, a type of fat that protects against atherosclerosis, were higher 3 Also, long-term sugar control, which can be measured by
checking for the amount of glycosylated hemoglobin HbA1c, was better in people on the low-carbohydrate diet However, it remains unclear whether these beneficial effects would continue after 1 year At present, the risks of obesity are well known, and the benefits of weight loss by traditional low-calorie, low-fat, and high-complex carbohydrate diets are also well documented Future research will clarify the long-term outcomes of a low-carbohydrate diet for achieving and maintaing a healthy weight together with the effects on the heart and other systems of the body
References
1 Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS, Szapary PO, Rader DJ, Edman JS, Klein S A randomized trial of a low-carbohydrate diet for obesity N Engl J Med 348:20822090; 2003 PubMed 2 Samaha FF, Iqbal N, Seshadri P, Chicano KL, Daily DA, McGrory J, Williams T, Williams M, Gracely EJ, Stern L A low-carbohydrate as compared with a low-fat diet in severe obesity N Engl J Med 348:2074 2081; 2003 PubMed 3 Stern L, Iqbal N, Prakash Seshadri, Chicano KL, Daily DA, McGrory J, Williams T, Williams M, Gracely EJ, Samaha FF The effects of low-carbohydrate versus conventional weight loss diets in
severely obese adults: one-year follow-up of a randomized trial Ann Intern Med 140:778785; 2004 PubMed
Box 1: The liver buffers glucose levels
The liver receives glucose-rich blood from the digestive tract via the portal vein Figure 3 The liver has a high amount of GLUT2 transporters that do not need the presence of insulin to transport glucose into the liver cells GLUT2 has a low affinity for glucose which enables a rapid influx of glucose when sugar levels are high Therefore, in the liver, levels of glucose inside and outside the cell can become equal an equilibrium is reached The first step for trapping glucose inside the cell involves phosphorylation to produce glucose-6-phosphate G6P The liver differs from the rest of the body in that it uses the enzyme glucokinase, rather than hexokinase Glucokinase can produce G6P at a faster rate and also is not inhibited by its product this is because in the liver, G6P can be channeled into making glycogen Glucose and insulin both modulate metabolic enzymes in such a way that glycogen formation is promoted This drives forward the process of bringing more glucose into the liver Insulin promotes glycogen synthesis by stimulating glycogen
synthetase and inhibiting glycogen phosphorylase
Link Roundup
The glycemic index [wwwjoslinharvardedu/education/library/glycemic_indexshtml], Joslin Diabetes Center, Boston
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The Story of Insulin
Insulin Synthesis
The insulin-making cells of the body are called beta cells, and they are found in the pancreas gland These cells clump together to form the islets of Langerhans, named for the German medical student who described them The synthesis of insulin begins at the translation of the insulin gene, which resides on chromosome 11 During translation, two introns are spliced out of the mRNA product, which encodes a protein of 110 amino acids in length This primary translation product is called preproinsulin and is inactive It contains a signal peptide of 24 amino acids in length, which is required for the protein to cross the cell membrane Once the preproinsulin reaches the endoplasmic reticulum, a protease cleaves off the signal peptide to create proinsulin Proinsulin consists of three domains: an amino-terminal B chain, a carboxyl-terminal A chain, and a connecting peptide in the middle known as the C-peptide Within the endoplasmic
reticulum, proinsulin is exposed to several specific peptidases that remove the C-peptide and generate the mature and active form of insulin In the Golgi apparatus, insulin and free C-peptide are packaged into secretory granules, which accumulate in the cytoplasm of the beta cells Exocytosis of the granules is triggered by the entry of glucose into the beta cells The secretion of insulin has a broad impact on metabolism
Insulin Structure
In 1958, Frederick Sanger was awarded his first Nobel Prize [http://wwwnobelse/chemistry/ laureates/1958/] for determining the sequence of the amino acids that make up insulin This marked the first time that a protein had had the order of its amino acids the primary sequence determined Insulin is composed of two chains of amino acids named chain A 21 amino acids and chain B 30 amino acids that are linked together by two disulfide bridges There is a 3rd disulfide bridge within the A chain that links the 6th and 11th residues of the A chain together In most species, the length and amino acid compositions of chains A and B are similar, and the positions of the three disulfide bonds are highly conserved For this reason, pig insulin can be used to
replace deficient human insulin levels in diabetes patients Today, porcine insulin has largely been replaced by the mass production of human proinsulin by bacteria recombinant insulin Insulin molecules have a tendency to form dimers in solution, and in the presence of zinc ions, insulin dimers associate into hexamers Whereas monomers of insulin readily diffuse through the blood and have a rapid effect, hexamers diffuse slowly and have a delayed onset of action In the design of recombinant insulin, the structure of insulin can be modified in a way that reduces the tendency of the insulin molecule to form dimers and hexamers but that does not interrupt binding to the insulin receptor In this way, a range of preparations of insulin is made, varying from short acting to long acting
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Insulin secretion
Rising levels of glucose inside the pancreatic beta cells trigger the release of insulin:
1
Glucose is transported into the beta cell by type 2 glucose transporters GLUT2 Once inside, the first step in glucose metabolism is the phosphorylation of glucose to produce glucose-6-phosphate This step is catalyzed by glucokinase–it is the rate-limiting
step in glycolysis, and it effectively traps glucose inside the cell As glucose metabolism proceeds, ATP is produced in the mitochondria The increase in the ATP:ADP ratio closes ATP-gated potassium channels in the beta cell membrane Positively charged potassium ions K are now prevented from leaving the beta cell The rise in positive charge inside the beta cell causes depolarization Voltage-gated calcium channels open, allowing calcium ions Ca2 to flood into the cell The increase in intracellular calcium concentration triggers the secretion of insulin via exocytosis There are two phases of insulin release in response to a rise in glucose The first is an immediate release of insulin This is attributable to the release of preformed insulin, which is stored in secretory granules After a short delay, there is a second, more prolonged release of newly synthesized insulin Once released, insulin is active for a only a brief time before it is degraded by enzymes Insulinase found in the liver and kidneys breaks down insulin circulating in the plasma, and as a result, insulin has a half-life of only about 6 minutes This short duration of action allows rapid changes in the circulating levels
of insulin
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Introduction to Diabetes
Insulin Receptor
The net effect of insulin binding is to trigger a cascade of phosphorylation and dephosphorylation reactions These actions are terminated by dephosphorylation of the insulin receptor Similar to the receptors for other polypeptide hormones, the receptor for insulin is embedded in the plasma membrane and is composed of a pair of alpha subunits and a pair of beta subunits Figure 1 The alpha subunits are extracellular and contain the insulin-binding site The beta subunits span the membrane and contain the enzyme tyrosine kinase Kinases are a group of enzymes that phosphorylate proteins the reverse reaction is catalyzed by a group of enzymes called phosphatases
Figure 1: The insulin receptor The insulin receptor is a tyrosine kinase receptor and is composed of a pair of alpha subunits and a pair of beta subunits Insulin binds to the alpha subunits and induces a conformational change that is transmitted to the beta subunits that autophosphorylate and initiate a cascade of phosphorylation and dephosphorylation reactions
Insulin binding to the alpha subunits induces a conformational change that is
transmitted to the beta subunits and causes them to phosphorylate themselves autophosphorylation A specific tyrosine of each beta subunit is phosphorylated along with other target proteins, such as insulin receptor substrate IRS As these and other proteins inside the cell are phosphorylated, this in turn alters their activity, bringing about the wide biological effects of insulin
Insulin Action
The binding of insulin results in a wide range of actions that take place over different periods of time Almost immediately, insulin promotes the uptake of glucose into many tissues that express GLUT4 glucose transporters, such as skeletal muscle and fat Insulin increases the the activity of these transporters and increases their numbers by stimulating their recruitment from an intracellu1-19
Diabetes
Introduction to Diabetes lar pool to the cell surface Not all tissues require insulin for glucose uptake Tissues such as liver cells, red blood cells, the gut mucosa, the kidneys, and cells of the nervous system use a glucose transporter that is not insulin dependent Over minutes to hours, insulin alters the activity of various enzymes as a result of changes in their phosphorylation status
Over a period of days, insulin increases the amounts of many metabolic enzymes These reflect an increase in gene transcription, mRNA, and enzyme synthesis
Link Roundup
Read more about Insulin on the Bookshelf
In Human Molecular Genetics 2, see the post-translation processing [http://wwwncbinlmnihgov/books/bvfcgi?callbvView ShowSectionridhmgfiggrp50] and the primary structure [http://wwwncbinlmnihgov/books/bvfcgi?callbvView ShowSectionridhmgfiggrp51] of insulin In Stryers Biochemistry, read about the receptors that contain tyrosine kinase domains [http://wwwncbinlmnihgov/books/bvfcgi? callbvViewShowSectionridstryersection20932101] | See the release of insulin [http://wwwncbinlmnihgov/books/bvfcgi? callbvViewShowSectionridstryerfiggrp4354], insulin crystals [http://wwwncbinlmnihgov/books/bvfcgi?callbvView ShowSectionridstryerfiggrp288], and the synthesis of proinsulin by bacteria [http://wwwncbinlmnihgov/books/bvfcgi?callbv ViewShowSectionridstryerfiggrp828]
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Source:ncbi.nlm.nih.gov
