Blood glucose and diabetes

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{{Poul-Erik_Paulev|27}} <div class="Section1"> ''<span lang="EN-US">'''Study Objectives'''</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span><span lang="EN-US">To ''define'' glicentin, gluconeogenesis, glycogenolysis, glycolysis, hyperglycaemia, hypoglycaemia, incretins, insulin antagonists, paracrine secretion, primary and secondary diabetes mellitus.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span><span lang="EN-US">To ''describe'' the structural and functional characteristics of the Langerhans islets with cell types and hormones produced. To describe the incretin effect, insulin effects, the insulin receptor, and the glucose transporter. To describe disorders of the different cell types and their clinical picture. To describe methods for evaluation of the glucose combustion.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span><span lang="EN-US">To ''draw'' oral and intravenous glucose tolerance curves with linear and logarithmic ordinates for blood glucose concentration.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span><span lang="EN-US">To ''explain'' the biosynthesis and the effects of insulin, glucagon, pancreatic polypeptide (PP) and somatostatin. To explain the glucose metabolism and the control of blood glucose in the fed and the fasting state.<span style="mso-spacerun: yes"> </span>To explain the consequences and the therapy of high and low blood glucose disorders.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span><span lang="EN-US">To ''use'' the above concepts in problem solving and in case histories. </span> ''<span lang="EN-US">'''Principles'''</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>''<span lang="EN-US">The physiological principle in treatment of diabetes is to inject a fast-acting insulin three times a day just before meals and a slow-acting insulin at night.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>''<span lang="EN-US">Insulin promotes the storage of energy, the synthesis of glycogen, mRNA and proteins.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>''<span lang="EN-US">Certain major tissues (kidney, brain and intestine) are insensitive to the direct action of insulin.</span>'' ''<span lang="EN-US">'''Definitions'''</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Glicentin</span>'''<span lang="EN-US"> is intestinal glucagon. Glicentin is built up from 69 amino acids in contrast to pancreatic glucagon, which consists of 29 amino acid moieties.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Gluconeogenesis</span>'''<span lang="EN-US"> refers to formation of new glucose from glycogenic amino acids, lactate, glycerol and pyruvate.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Glycogenolysis</span>'''<span lang="EN-US"> refers to glycogen breakdown to glucose in the liver.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Glycolysis</span>'''<span lang="EN-US"> refers to anaerobic breakdown of glycogen.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Hyperglycaemia</span>'''<span lang="EN-US"> is a condition, where the blood glucose is above 6.7 mM.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Hypoglycaemia</span>'''<span lang="EN-US"> refers to a serious condition, where the blood glucose is below 2 mM.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Incretins</span>'''<span lang="EN-US"> are hormones, which strongly potentiates the insulin secretion induced by the rising blood [glucose]. The incretins cause a much larger insulin secretion than the iv. administration of glucose, even at the same rise in blood [glucose]. This extra insulin secretion is called the ''incretin effect''.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Ketogenesis</span>'''<span lang="EN-US"> refers to accelerated lipolysis with liberation of free fatty acids to the blood. Free fatty acids are broken down to fatty acyl carnitine within the liver cells, and this molecule is converted into acetyl CoA, which in turn reach the mitochondria, where ketone bodies are formed. </span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Paracrine secretion</span>'''<span lang="EN-US"> is a release of signal molecules to neighbour cells.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Insulin antagonists</span>'''<span lang="EN-US"> are hormones opposing the effect of insulin: Pancreatic and intestinal (glicentin) glucagon, ACTH, growth hormone.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Primary diabetes mellitus </span>'''<span lang="EN-US">refers to all cases, where the cause is not fully explained.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Secondary diabetes mellitus</span>'''<span lang="EN-US"> is caused by hypersecretion of one or more of the many catabolic hormones with hyperglycaemic effect (adrenaline, noradrenaline, glucagon, glucocorticoids and growth hormone) or by total destruction of the pancreas from pancreatitis or carcinoma. The hormone disorders are phaeochromocytoma, glucagonoma, Cushing&rsquo;s syndrome and acromegaly.</span> <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'''<span lang="EN-US">Somatostatin </span>'''<span lang="EN-US">(GHIH) is a multipotent hormone inhibitor consisting of a disulphide bridge and 14 amino acid units.</span> ''<span lang="EN-US">'''Essentials'''</span>'' <span lang="EN-US">This paragraph covers ''[http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#1.%20Glucose%20regulation%20in%20the%20fed%20state 1. the blood glucose regulation] in the fed state, ''as well as in ''[http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#2.%20Glucose%20regulation%20in%20the%20fasting%20state%20(rest%20and%20exercise 2. the fasting states]''.<span style="mso-spacerun: yes"> </span>Also ''[http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#3.%20The%20endocrine%20pancreas 3. The endocrine pancreas], ''and'' [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#4.%20Pancreatic%20exocrine%20control 4. Pancreatic exocrine control] ''is dealt with.</span> <span lang="EN-US">'''1. Glucose regulation in the fed state'''</span> <span lang="EN-US">In the ''absorptive state'' after a balanced meal, nutrients enter the blood and lymph from the gastrointestinal tract (as monosaccharides, triglycerides, and amino acids). All the blood passes directly to the liver, which converts most of the other monosaccharides into ''glucose.'' Much of the absorbed carbohydrate enters the liver cells, but little of it is oxidised; instead most is stored as glycogen. Absorbed glucose, which did not enter hepatocytes but remained in the blood, is stored as glycogen by muscle cells, or it may enter into adipose tissue. A large fraction is oxidised to CO₂ and water in the various cells of the body. Glucose is the major source of energy during the absorptive state. Homeostatic mechanisms maintain the plasma [glucose] within narrow limits in healthy humans, so that the energy needs during the postabsorptive state can be met by stored fuel.</span> <span lang="EN-US">A high glucose intake results in a high blood [glucose] or extracellular ''hyperglycaemia''. Hyperglycaemia increases insulin secretion from the </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells and inhibits glucagon secretion from the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells of the pancreatic islets. These hormones block ''hepatic glucose production ''by glycogenolysis and gluconeogenesis. ''Insulin secretion'' dominates over all ''insulin-antagonists ''(growth hormone, glucagon, cortisol and some catecholamines).<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">The sight and the smell of a meal triggers ''cephalic'' insulin secretion. When the meal reaches the intestine, several peptides of the ''incretin family'' are released; this is the ''intestinal ''secretion phase. Typical representatives of the ''incretin family ''are Gastric Inhibitory Peptide (GIP), glicentin (intestinal glucagon), and glucagon-like peptides (GLP-1 and -2). Incretins strongly potentate the insulin secretion induced by the rising blood [glucose]. The ''incretins ''cause a much larger insulin secretion than the iv. administration of glucose, even at the same rise in blood [glucose]. This extra insulin secretion is called the ''incretin effect''. The insulin released following a meal increases the storage rate of glucose-related energy in the liver, muscles and fat tissues. The storage effect is much larger than when glucose is administered intravenously.</span> <span lang="EN-US">Glucose is absorbed through the luminal membrane of the intestinal cells in ''glucose-Na⁺ transporter proteins''. The two substances pass through the basolateral membrane via separate routes: Glucose passes in a special glucose-transporter, and Na⁺ is transferred by the Na⁺-K⁺&#x2011;pump. Glucose transport proteins and insulin receptors are described in [http://www.mfi.ku.dk/ppaulev/chapter1/kap%201.htm Chapter 1].</span> <span lang="EN-US">The filtration flux for glucose (mmol per min) increases proportionally to the concentration in the blood (as for all other filtered substances). Normally, all glucose is reabsorbed in the first part of the proximal renal tubules with a T_max of 1.8 mmol per min or 320 mg per min.</span> <span lang="EN-US">In other words, the passage fraction falls from one to zero already halfway through the proximal tubules. The excretion flux for glucose is ''zero'' in healthy humans.</span> <span lang="EN-US">Glucose appears in the urine of diabetics, who have a blood [glucose] exceeding the ''appearance thres&shy;hold ''(10 mM).</span> <span lang="EN-US">Reabsorption of glucose over the luminal membrane of the proximal tubule cell takes place through the ''glucose-Na⁺ transporter''.</span> <span lang="EN-US">'''2. Glucose regulation in the fasting state (rest and exercise''')</span> <span lang="EN-US">We keep our blood [glucose] surprisingly constant around the fasting level, considering the wide variety of daily activities.<span style="mso-spacerun: yes"> </span></span> ''<span lang="EN-US">Glucose production</span>''<span lang="EN-US"> (gluconeogenesis and glycogenolysis) must equal ''glucose combustion ''in the fasting state. Thus, a precise relation must exist between the secretion of insulin and glucagon from the pancreatic islets.</span> <span lang="EN-US">In the fasting state hepatic ''glycogenolysis'' produces most of the glucose and the remaining glucose is produced by ''gluconeogenesis''. Hepatic glucose is produced by ''glycogenolysis ''(glycogen breakdown to glucose) and by ''gluconeogenesis ''(glucose formation from glycogenic amino acids, lactate, glycerol, and small amounts of pyruvate. Muscle glycogen cannot deliver glucose to the blood, since muscle tissues lack ''glucose-6-phosphatase''.</span> <span lang="EN-US">In the fasting condition a healthy adult has a blood [glucose] of ''4.5-5.6 ''mM. With an average [glucose] of 4 mM in 15 l of extracellular fluid volume (ECV), therefore, the total glucose content in ECV is 60 mmol or 10.8 g (2 teaspoons of sugar). This amount is equal to the glucose eliminated in one hour at rest (60 mmol each hour), but during maximum exercise that same person may use ''five''''' '''times more glucose.</span> <span lang="EN-US">The CNS and the erythrocytes neither synthesise nor store glucose, which is their primary fuel. Any surplus of glucose is deposited as liver and muscle ''glycogen''. The liver cells contain an especially ''efficient glucose transporter'' (GLUT 2), and its ''glucose uptake rate ''cannot be increased further by insulin or by other hormones.</span> <span lang="EN-US">Any small ''fall ''in blood glucose releases more glucagon. During fasting ''glycogenolysis, gluconeogenesis, and lipolysis ''are dominant. If a normal person does not eat for 24-48 hours the CNS cells revert to combustion of ketone bodies, and a reversible condition that is similar to diabetes develops (''hunger diabetes'').</span> <span lang="EN-US">''Exercise''</span> <span lang="EN-US">The exercise stress on the hypothalamus increases the activity of the ''sympathoadrenergic system, ''which includes increased secretion of adrenaline from the adrenal medulla. Sympathoadrenergic activity inhibits the ''insulin secre&shy;tion'' from the </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells. Sympathetic activity also increases hepatic glucose production.</span> <span lang="EN-US">We tend to increase glucagon secretion only if the blood [glucose] falls. A slight fall in blood [glucose] can occur both during exercise bouts and during prolonged exercise.</span> <span lang="EN-US">During exercise the blood [glucose] is maintained rather constant by bihormonal''' '''interplay between insulin and glucagon.</span> <span lang="EN-US">Generally, an increasing demand of more energy elicits increased glycogenolysis, lipolysis, and increased gluconeogenesis caused by insulin-antagonistic hormones (catecholamines, glucagon, cortisol, and growth hormone).</span> <span lang="EN-US">Adrenaline inhibits the insulin and stimulates the glucagon secretion, so the blood [glucose] increases.</span> ''<span lang="EN-US">Somatotropin </span>''<span lang="EN-US">&#x2011; human growth hormone (GH) &#x2011; is an ''insulin-antagonist, ''but together with insulin probably the most important ''anabolic hormone.''</span> <span lang="EN-US">Conditions where energy sources are lacking are hypoglycaemia, hunger, fasting state, exhaustion, and stress. These conditions trigger the release of GRH from the hypothalamus, which in turn stimulates the release of GH from the hypophysis. This hormone has a ''tropic effect ''on the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US"> -cells of the pancreatic islets. GH releases glucagon from these cells, just as sympathetic stimulation from the hypothalamus does.</span> <span lang="EN-US">GH increases blood [glucose] by increasing ''hepatic glucose production ''(glycogenolysis but not its gluconeogenesis) and by inhibiting the insulin sensitivity of the muscle cells and thus reduces their glucose uptake. GH also has the same effect on fat cells, mobilising fatty acids and glycerol. GH stimulates protein synthesis, mitoses, chondrogenesis, ossification, and phosphate balance, while increasing glycolysis (ie, anaerobic breakdown of glycogen).</span> ''<span lang="EN-US">Glucocorticoids</span>''<span lang="EN-US"> are insulin-antagonists. They stimulate the ''hepatic glucose production ''(glycogenolysis and gluconeogenesis) but inhibit the cellular glucose uptake. Glucocorticoids are ''permissive ''and ''potentiating'' for catecholamines and glucagon.</span> ''<span lang="EN-US">Catecholamines</span>''<span lang="EN-US"> (adrenaline &amp; noradrenaline) are ''insulin-antagonists. ''Adrenaline ''stimulates hepatic glucose production'' (glycogenolysis). Catecholamines also stimulate lipolysis. The increase in mitochondrial oxygen uptake by T₃/T₄ is potentates by catecholamines.</span> <span lang="EN-US">''The glucostat''</span> ''<span lang="EN-US">Glucose sensitive neurons</span>''<span lang="EN-US"> in the hypothalamus (the ''glucostatic centre'') react to hypoglycaemia by releasing glucagon from the pancreatic </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells and catecholamines from the adrenal medulla by action of the sympathetic system.</span> <span lang="EN-US">The glucostatic centre also reacts to hyperglycaemia to release insulin from pan&shy;creatic </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells, and to activate hepatic glycogen synthesis by vagal stimuli. Insulin promotes the entry of glucose into tissues, including the neurons of the hypothalamic glucostatic centre (but in no other brain neurons). A balanced blood [glucose] is achieved by sympathetic signals stimulating hepatic glucose production. This balance theory is called the glucostatic theory. In the glucostatic theory the hypothalamus is considered a glucostat and the liver is a unique glucose exchanger, due to the portal system and the hepatic glucose-6-phosphatase. Leptin is dealt with in [http://www.mfi.ku.dk/ppaulev/chapter20/kap%2020.htm Chapter 2]0.</span> <span lang="EN-US">Since the hypophysis hormones ACTH and GH are insulin-antagonists the net effect of the hypophysis, when not balanced by a normal pancreatic insulin secretion, is a reduced glucose tolerance.</span> <span lang="EN-US">'''3. The endocrine pancreas'''</span> <span lang="EN-US">The endocrine pancreas or the pancreatic islets are synonyms for the produc&shy;tion site of four polypeptide hormones: Glucagon, insulin, somatostatin, and pancreatic polypeptide (PP).</span> <span lang="EN-US">The one million islets of Langerhans are discrete structures scattered throughout the pancreas, but which only comprise 1% of its total weight. The islets are arranged along fenestrated capillaries, so that the hormones can pass easily to the portal blood. The islets of Langerhans receive both sympathetic (adrenergic) and parasym&shy;pathetic (cholinergic) fibres.</span> <span lang="EN-US">The membranes of the islet cells contain gap junctions between neighbour cells, so hormones from one cell can act on its neighbour (paracrine action). Gap junctions allow passage of small molecules from one islet cell to its neighbour. In many pancreatic lobules, the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US"> - </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US"> - and </span><span lang="EN-US" style="font-family:Symbol">d</span><span lang="EN-US"> - cells form a paracrine syncy&shy;tium.</span> <span lang="EN-US">''3 a. Glucagon''</span> <span lang="EN-US">The </span><span lang="EN-US" style="font-family: Symbol">a</span><span lang="EN-US">-cells of the pancreatic islets is the source of pancreatic glucagon. Glucagon stimulates adenylcyclase in the hepatocytes. This enzyme activates phosphorylase that breaks down glycogen. Actually, glucagon triggers a glycogenolytic cascade, so those considerable amounts of glucose are released in response to the fall in blood glucose. In addition, glucagon stimulates the hepatic production of glucose (gluconeogenesis) from glycerol, alanine and lactate. Glucagon is a direct antagonist to insulin, being catabolic in its actions (gluconeogenetic, glycogenolytic, lipolytic &amp; ketogenic, and deaminating amino acids).</span> <span lang="EN-US">Intestinal glucagon (glicentin) is built up from 69 amino acids. The glucagon from the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells of the pancreatic islets only contains 29 of the 160 amino acid residues in pro-glucagon. Conditions where there is intracellular lack of glucose (hunger, insulin deficiency, protein rich meals, and amino acid infusion) liberate glucagon from the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells of the pancreatic islets to the pancreatic vein and then to the portal vein. Glucagon stimulates ketogenesis (formation of ketone bodies). High blood [glucose] and [FFA] inhibit glucagon secretion.</span> <span lang="EN-US">Pancreatic and intestinal (glicentin) glucagon are hepatic insulin-antagonist. Glucagon stimulates hepatic glucose production by glycogenolysis in the hepatocytes and thus increases the blood [glucose].</span> <span lang="EN-US">Glucagon also stimulates gluconeogenesis from glycogenic amino acids in the liver and thus increases urea-genesis. Glucagon stimulates ketogenesis (formation of ketone bodies). In addition to the ketogenic effect, intestinal glucagon is a potent stimulator of insulin secretion - as are other members of the incretin family. Incretins act by increasing cAMP in the </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells.<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">''3 b. Insulin''</span> <span lang="EN-US">Banting shared the Nobel Prize with Macleod in 1923 for their work in identifying the role of insulin in the carbohydrate metabolism. Their research led to the practice of insulin therapy for diabetes.</span> <span lang="EN-US">Pre-proinsulin is the precursor of insulin. When pre&#x2011;proinsulin reaches the endoplasmic reticulum, enzymes separate the molecule from the signal molecule, to form proinsulin. In the Golgi apparatus enzymes cleave proinsulin to insulin (51 amino acids in two chains: A and B) and the C peptide (Connecting peptide). Insulin and C peptide are wrapped in the same secretion granule. The content of these secretion granules is expelled from the cell by exocytosis.</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>When the secretory granules release proinsulin to the portal blood and later the extracellular fluid volume (ECV), connecting peptide (C-peptide) and two amino acids breaks off. The split products are carried to the liver, where half of the insulin molecules are degraded and extracted. The degradation products are broken down and eliminated by the kidney. The kidneys only eliminate c-peptide and its rate of production reflects the rate of insulin secretion. Insulin contains 51 amino acid residues in two chains (m.w. 5734).</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>In healthy persons the blood glucose concentration, B-</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US">, is controlled exactly. The fasting value is within the range of 4-7 mM, with minimum individual variance from day to day, despite varying life conditions with food and exercise.</span> <span lang="EN-US">The liver is a glucose exchanger, because it absorbs glucose from the intestine, stores glucose as glycogen, and produce glucose from fat and protein residues (gluconeogenesis). The liver releases glucose to the ECV in exact proportion to the peripheral rate of glucose utilisation in the postabsorptive state (180-200 g per day).</span> <span lang="EN-US">The brain metabolism of a healthy standard person requires 100 g of glucose per day.<span style="mso-spacerun: yes"> </span>The brain glucose is totally oxidised, ir-regardless of the insulin status.</span> <span lang="EN-US">Each meal elicits a peak of insulin secretion, because of the rise in blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"><span style="mso-spacerun: yes"> </span>([[Image:fysiologi_paulev_27-1.jpg]] Fig. 27-1]). The blood [glucose] increases after a meal. Increasing [glucose] is a strong stimulus to the </span><span lang="EN-US" style="font-family: Symbol">b</span><span lang="EN-US">-cells of the pancreas. Glucose enters these cells through GLUT 2. The cells empty their granules into the ECV, and the granule dissolve immediately after entering the blood. This sequence of events supplies the blood with insulin, C-peptide and proinsulin in the ratio 19:19:1.</span> <span lang="EN-US">Insulin reduces the blood glucose for the following reasons: insulin increases the cell uptake of glucose (and potassium) in most tissues (adipocytes, heart and other muscle tissue). The exceptions are the brain, kidney and erythrocytes. The uptake capacity for glucose in hepatocytes is so large, that any insulin effect is immaterial.</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>Insulin promotes the formation of tissue stores from circulating nutrients (the actions are all anabolic). The insulin receptor is a tetrameric protein complex with two </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">a</span><span lang="EN-US">-units extracellularly, and two </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-units traversing the membrane of target cells (ie, skeletal muscle fibres, cardiac myocytes and adipocytes). The target cells contain the glucose transporter, GLUT-4. In the absence of insulin, all the GLUT-4 units are located in the intracellular vesicles. Insulin binding to the insulin-receptor activates the tyrosine kinase, which resides in the </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-units, and promotes the transport of GLUT-4 vesicles towards the surface of the cell, where they melt together with the membrane. This phenomenon increases the number of glucose-channels through the membrane and thus promotes glucose uptake into target cells. Finally, the insulin-receptor complex is internalised by the cell, insulin is broken down and the insulin-receptor recycles to the cell surface for further use.</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>Glucose is stored in the muscle cells as glycogen, used in the Krebs cycle or it is broken down to lactate.</span> <span lang="EN-US">In the fat cells glucose is utilised as a substrate for triglycerides synthesis. In the post-prandial phase, lipolysis liberates fatty acids (FFA) from triglyceride together with glycerol. Glycerol and lactate are substrates for hepatic gluconeogenesis.</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-1.jpg]] Fig. 27-1]<nowiki>: Effects of insulin on target cells.</nowiki></span>''' <span lang="EN-US">Falling blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"> is called hypoglycaemia, which activates the sympathoadrenergic system and deplete the glucose-dependent brain for its only fuel. Accordingly, the hypoglycaemia causes sympathoadrenergic (sweating, hunger, tremor, tachycardia), and cerebral manifestations (anxiety, disorientation, cramps, and unconsciousness). The clinical picture is that of hypoglycaemic shock.</span> <span lang="EN-US">Insulin also increases the rate of glycogen synthesis in the liver and muscles and inhibits the rate of gluconeogenesis. Insulin is a direct antagonist to glucagon being anabolic in its actions (increased glucose entry to cells, increased glycogen and lipid synthesis, decreased protein catabolism and ketogenesis).</span> <span lang="EN-US">Glucose-evoked insulin secretion is the result of a chain of events in the pancreatic </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell (Fig. 27-2).</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-2.jpg]] Fig. 27-2]<nowiki>: Insulin release from pancreatic </nowiki></span>''''''<span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell.</span>''' <span lang="EN-US"><span style="mso-spacerun: yes"> </span>1. <span style="mso-tab-count:1"> </span>The glucose uptake takes place through a specific transporter protein (GLUT-2). The pancreatic </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell membrane contains several K⁺ channels, of which two are directly involved. This is the K⁺-ATP channel and the maxi-K⁺ channel (Fig. 27-2).</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>2. <span style="mso-tab-count:1"> </span>The hyperglycaemia accelerates the glucose uptake and metabolism and thus increases the ATP/ADP ratio.</span> <span lang="EN-US">3. <span style="mso-tab-count:1"> </span>Increased ATP closes the K⁺-ATP channels, so the cell depolarises (hypopolarises). During hypopolarisation from the normal resting membrane potential of -70 mV, a threshold is reached at - 50 mV, where the voltage dependent Ca²⁺ channels open.</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>4. <span style="mso-tab-count:1"> </span>The Ca²⁺ influx triggers exocytosis of insulin and C-peptide containing granules following vesicular fusion with the cell membrane.</span> <span lang="EN-US"><span style="mso-spacerun: yes"> </span>5. <span style="mso-tab-count:1"> </span>Normally, the maxi-K+ channel and other K+ channels stop depolarisation. When intracellular [Ca²⁺] and [K⁺] has increased, it opens the maxi-K⁺ channel. The K⁺ efflux restores the resting membrane potential (- 70 mV) towards the equilibrium potential of K⁺ (-100 mV).</span> <span lang="EN-US">Insulin is a vital hormone. Blood from the pancreas passes through the liver, where insulin promotes the produc&shy;tion of glycogen from the recently absorbed glucose. The liver destroys a substantial amount of the insulin, whereas the C-peptide passes the liver undisturbed. The plasma [C-peptide] is thus a good estimate of insulin secretion. Insulin can now be synthesized from genetically modified micro-organisms.</span> <span lang="EN-US">Insulin is an anabolic hormone.</span> <span lang="EN-US">Insulin reduces the blood [glucose] because it increases glycogen synthesis in the liver and muscles. Insulin increases the uptake of glucose through GLUT 4 (in adipocytes, heart and skeletal muscles). Insulin inhibits the gluconeogenesis from glycogenic amino acids in the liver.</span> <span lang="EN-US">Insulin promotes the storage of energy, the synthesis of glycogen, mRNA and proteins. Insulin thus reduces urea-genesis.</span> <span lang="EN-US">Insulin promotes lipogenesis in the fat stores; however, it inhibits lipolysis. It may be noted that the glycerol portion of the triglyceride molecule is a derivative of glucose.</span> <span lang="EN-US">Insulin increases the synthesis of cholesterol in the liver, in particular the rate of VLDL formation (Very Low Density Lipoprotein). The dangerous cholesterol fraction is LDL (Low Density Lipoprotein).</span> <span lang="EN-US">Insulin increases the GLUT 4 transfer of glucose and K⁺ into the muscle cell interior.</span> <span lang="EN-US">Certain major tissues (kidney, brain, and intestine) are insensitive to the direct action of insulin.</span> <span lang="EN-US">''3 c. Somatostatin''</span> <span lang="EN-US">D-cells or </span><span lang="EN-US" style="font-family:Symbol">d</span><span lang="EN-US">-cells are the source of somatostatin, a potent and multipotent hormone inhibitor. Somatostatin contains a disulphide bridge and 14 amino acid molecules. Somatostatin produced in the islets inhibits the local secretion of the other islet hormones, while glucagon stimulates the local release of insulin and somatostatin. Somatostatin is also produced in the hypothalamus, where it functions as the Growth Hormone Inhibiting Hormone (GHIH). Pancreatic somatostatin is released in response to high blood [glucose] and [alanine]. Somatostatin inhibits the secretion of the gastrointestinal tract (but not its motility) and functions as a synaptic transmitter in the CNS. Persons with somatostatin-producing tumours develop diabetes and gallstones.</span> <span lang="EN-US">GHIH is synthesized both in the hypothalamic-pituitary system and in the pancreatic islets. The D-cells of the pancreatic islets of Langerhans produce GHIH, which controls the function of the other islet cells by paracrine action. Somatostatin is a multipotent hormone inhibi&shy;tor. Somatostatin inhibits Somatotropin (GH) but also TSH, insulin, and glucagon. Somatostatin blocks the gastrin secretion in the gastric antrum. Somatostatin inhibits the secretion of digestive fluids, but increases gastrointestinal motility.</span> <span lang="EN-US">''3 d. Pancreatic polypeptide''</span> <span lang="EN-US">The cells responsible for pancreatic polypeptide (PP) secretion are particularly abundant in the head of the pancreas. PP contains 36 amino acid residues in a linear polypeptide. The plasma [PP] increase markedly after a protein rich meal, but it is not released by alanine infusion. The PP secretion is increased by exercise (with high plasma [alanine]), by fasting and by hyperglycaemia. The plasma [PP] is suppressed by glucose infusion. PP inhibits the exocrine pancreas and reduces the gallbladder contractions. This is an appropriate response during exercise and fasting, where any reduction in blood glucose would trigger a PP release.</span> <span lang="EN-US">Meals, rich in protein and fat, release pancreatic polypeptides (from the PP-cells).</span> <span lang="EN-US">Pancreatic polypeptide inhibits both enzyme secretions from the pancreas and the emptying of bile into the small intestine. This leads to a delay in the absorption of nutrients including glucose.</span> <span lang="EN-US">Patients with pancreatic islet cell neoplasm have elevated plasma [PP].</span> <span lang="EN-US">'''4. Pancreatic exocrine control'''</span> <span lang="EN-US">Endocrine glandular tissue is localised in the Langerhans islets that produces insulin in the </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells, glucagon in the </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells, somatostatin (GHIH) plus gastrin from the </span><span lang="EN-US" style="font-family:Symbol">d</span><span lang="EN-US">- and G-cells, and pancreatic polypeptide (PP) from the P-cells ([[Image:fysiologi_paulev_27-3.jpg]] Fig. 27-3]). Bombesin, galanin, and neuropeptides are present in pancreatic neurons and act as transmitters.</span> <span lang="EN-US">Stimulation of vagal fibres to the pancreas enhances the rate of enzyme secretion into the pancreatic juice. Stimulation of sympathetic fibres reduces bloodflow to the pancreas, and thus inhibits pancreatic secretion. Gastrin enhances enzyme secretion and insulin potentiates the effect, whereas somatostatin inhibits secretion from both acinar and ducts cells (Fig. 27-3: - all).</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-3.jpg]] Fig. 27-3]<nowiki>: Liberation of pancreatic islet hormones.</nowiki></span>''' ''<span lang="EN-US">'''Pathophysiology'''</span>'' <span lang="EN-US">Diabetes mellitus (DM)</span> <span lang="EN-US">DM is a collective term for a multitude of metabolic disorders, where lack of insulin (type I diabetes) or insulin resistance (type II) dominates.</span> ''<span lang="EN-US">Insulin resistance</span>''<span lang="EN-US"> is defined as insufficient sensitivity to insulin.</span> <span lang="EN-US">The diabetic condition is characterized by an abnormal glucose tolerance that is documented by the use of a glucose tolerance test.<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">Besides hyperglycaemia, the overall phenomena in the diabetic condition are ''protein depletion ''and ''increased lipolysis ''with deposition of lipids in the vascular walls of the brain, heart, kidneys, eyes and muscles.</span> <span lang="EN-US">All cases of DM where the cause is not fully explained are termed ''primary ''DM, whereas ''secondary ''DM is explainable and sometimes directly curable.</span> <span lang="EN-US">Secondary DM is caused by hypersecretion of one or more of the many catabolic hormones with hyperglycaemic effect (adrenaline, noradrenaline, glucagon, glucocorticoids and growth-hormone, HG) or by total destruction of the pancreas from pancreatitis or carcinoma. The hormone disorders are phaeochromocytoma, glucagonoma, Cushing&rsquo;s syndrome and acromegaly.</span> <span lang="EN-US">Most of the patients with primary DM can be classified into the two groups already presented above Insulin-Dependent DM (IDDM) or type I diabetes, and Non-Insulin-Dependent DM (NIDDM) or type II diabetes.</span> <span lang="EN-US">This paragraph deals with ''[http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#1.%20IDDM%20or%20Type%20I%20diabetes 1. IDDM], [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#2.%20NIDDM%20or%20Type%20II%20diabetes 2. NIDDM], [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#3.%20Insulin%20shock%20(hypoglycaemia) 3. Insulin shock] (hypoglycaemia), [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#4.%20Oral%20and%20intravenous%20glucose%20tolerance%20tests 4. Oral and intrveneous glucose tolerance tests], [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#5.%20Treatment%20of%20diabetes%20mellitus 5. treatment of diabetes mellitus], and [http://www.mfi.ku.dk/ppaulev/chapter27/kap%2027.htm#6.%20Summary%20of%20the%20diabetic%20condition 6. Summary of the diabetic condition.]''</span> <span lang="EN-US">'''1. IDDM or Type I diabetes'''</span> <span lang="EN-US">The presentation of IDDM is typically a young person with a few week history. This is a serious, life threatening metabolic disease, where continuation of life depends upon insulin treatment. The first treatment with insulin took place in Canada (1922). Until then these patients died within half a year in ketoacidotic coma. Persons, often with hereditary predisposition, are suddenly attacked by autoimmune destruction of ''all ''</span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells in the pancreatic islets, which results in the complete absence of insulin. This autoimmune destruction occurs more often in populations, where breast feeding is unpopular, and protein-rich cow's milk is used generally.</span> <span lang="EN-US">Lack of insulin leads to extracellular hyperglycaemia, and increased lipolysis.</span> <span lang="EN-US">The classical triad is:</span> <span lang="EN-US">1. <span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> <span lang="EN-US">Polyuria (osmotic diuresis due to extracellular hyperglycaemia and glucosuria).</span> <span lang="EN-US">2. <span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> <span lang="EN-US">Polydipsia and thirst due to the loss of salt and water.</span> <span lang="EN-US">3. <span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> <span lang="EN-US">Weightless due to extracellular fluid volume (ECV) depletion and the breakdown of tissue stores (ie catabolic effect of insulin deficiency) with rapid wasting.</span> <span lang="EN-US">The intracellular lack of glucose activates glycogenolysis in the liver and muscle cells; lipolysis and muscular proteolysis is accelerated. The liberated free fatty acids (FFA) are converted to ketone bodies, whereby a metabolic acidosis (ketoacidosis) is produced.</span> <span lang="EN-US">A patient with a blood (glucose) above 25 mM loses consciousness and to such degrees that contact is impossible and reactions to pain are absent (coma).</span> <span lang="EN-US">Diabetic ketoacidosis is a condition of insulin deficiency causing increased hepatic ketogenesis. This condition of uncontrolled catabolism occurs in IDDM, only.</span> <span lang="EN-US">In a young person, the first sign of IDDM can be coma with diabetic ketoacidosis - a life-threatening condition, if the patient is alone. This is particularly likely, when the patient is under the stress of intercurrent illness such as infection with high fever. Also a recognized IDDM patient can be hit by ketoacidosis during intercurrent illness, where his insulin demand is increased, or the patient may take too little insulin because of lost appetite or for any other reason.<span style="mso-spacerun: yes"> </span></span> ''<span lang="EN-US">Insulin deficiency</span>''<span lang="EN-US"> has two consequences. First of all, the hepatic glucose release accelerates, and secondly the uptake of glucose by muscle and fat cells in the periphery is reduced. Progressive hyperglycaemia causes osmotic diuresis with loss of salt and water. The abnormally low ECV is termed the dehydrate state, and with falling blood volume also renal bloodflow falls. Insulin deficiency also accelerates the lipolysis (Fig. 27-4).</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-4.jpg]] Fig. 27-4]<nowiki>: The development of ketoacidosis during insulin deficiency (FFA = free fatty acids).</nowiki></span>''' <span lang="EN-US">Triglycerides are liberated from adipose tissue, and the concentration of free fatty acids (FFA) in the blood is elevated. FFA are broken down to fatty acyl carnitine within the liver cells, and this molecule is converted to acetyl CoA, which in turn reach the mitochondria, where ketone bodies (aceto-acetate, acetone, </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-hydroxybutyrate) are formed (Fig. 27-4).</span> <span lang="EN-US">The breath of the patient smell by acetone, and there is ketosis in the urine. The concentration of ketone bodies in the blood passes ''5 mM'', and when pH falls below 7, there is life-threatening or terminal coma. The condition is called an acute metabolic acidosis, characterized by a negative base excess. The patient tries to compensate the metabolic acidosis by hyperventilation, so-called Kussmaull-breathing.<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">Most patients with recent IDDM have circulating antibodies to islet cells, and tend to develop other organ-specific autoimmune disorders (Addison disease, Hashimotos thyroiditis and pernicious anaemia). Identical twins show a 40% concordance in developing IDDM, so life-style must also play a role. There is an association with HLA-DR4, if also HLA-B8 or HLA-DR3 is present.</span> <span lang="EN-US">'''2. NIDDM or Type II diabetes'''</span> <span lang="EN-US">This is a frequent type of DM in particular in populations with a sedentary life style and obesity. The incidence increases with age and development of obesity, which is reflected in the name ''maturity-onset diabetes''. The prevalence is high in Afro-Caribbean and Asian population groups. The onset of NIDDM is sometimes triggered by Intercurrent illness or by pregnancy, but not by immunological reactions.</span> <span lang="EN-US">NIDDM is a complex of polygenic disorders. Certain families show an autosomal dominance. the genetic defects differ and many mutations are known. One is the gene on chromosome 7, which code for ''glucokinase.''''' '''Identical twins show almost absolute concordance in development of NIDDM. The much more frequent ''type II diabetes ''(maturity-onset) is the result of ''insulin resistance''''' '''and </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell defects. Type II diabetes also occurs in younger persons, especially in persons with a ''high fat-low muscle mass''. A strong genetic element is always present, but ''inactivity ''and ''stress ''(an inactive life style with a low endurance capacity) seems to be involved in the development of type II diabetes. - Lack of exercise predisposes one to obesity, a condition that greatly decreases ''insulin sensitivity ''of the target cells (adipocytes, heart and skeletal muscle tissues). Reduced glucose combustion creates hyperglycaemia. The hyperglycaemia elicits insulin secretion from defective </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells in some patients, resulting in raised serum [insulin]. Since insulin is present, the acute complications such as ketonaemia and metabolic acidaemia (often found with IDDM) are rare in these patients. The high serum [insulin] may further down-regulate the activity of their ''insulin receptors. ''The insulin secreted in NIDDM patients does not increase the uptake of glucose as in normal persons. Many NIDDM patients need much more insulin for a given test effects than IDDM patients and healthy people.</span> <span lang="EN-US">An inactive life style for years, with redundant food intake, seems to be involved in the development of NIDDM in persons with a genetic predisposition. Lack of regular physical activity with development of overweight, increases the incidence if NIDDM. The ''impaired glucose tolerance ''is demonstrated by a ''glucose tolerance test''.</span> <span lang="EN-US">The insulin secretion is abnormal in patients with NIDDM, although they typically possess half of their </span>''<span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-cell mass</span>''<span lang="EN-US"> at autopsy. The destroyed </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-cells is filled with amyloid material (islet amyloid polypeptide, IAPP). IAPP is a possible antagonist to insulin, and explain some cases of ''insulin resistance''.</span> <span lang="EN-US">Many older patients with NIDDM have no symptoms, but a routine examination reveals glucosuria or a raised blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US">. Other patients are tired, have minor genital infections or sugar spots on their underwear. Some patients present with established ''late-complications ''such as retinopathy (blindness), nephropathy, arteriosclerotic disorders (cerebrovascular insults, myocardial infarction, intermittent claudication, gangrene), susceptibility to infection or neuropathy.</span> <span lang="EN-US">NIDDM can be caused, theoretically, by ''1. ''</span>''<span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell defects</span>''<span lang="EN-US"> including genetic defects, resulting in abnormal insulin production, or by ''2. target cell defects ''including receptor failure. The possible defective sites in 1. and 2. have one common denominator. They are all ''key proteins ''(hormone, receptors and transporters). Muscular activity is required to stimulate the normal production of ''key proteins''. NIDDM relates to inactive life style.</span> <span lang="EN-US">The basic problem is therefore possibly a genetically and activity dependent ''defect in key protein production ''in the cell interior. Actually, a genetic defect has just been demonstrated at certain steps of insulin action in a subset of patients of late-onset NIDDM.</span> <span lang="EN-US">'''3. Insulin shock (hypoglycaemia)'''</span> <span lang="EN-US">A high blood [insulin] will cause tissues to store away the available blood glucose rapidly, mainly through muscular GLUT 4, and stop simultaneously the production of new glucose.</span> <span lang="EN-US">A low blood glucose level elicits a large secretion of glucagon to the portal blood. Glucagon is the most important insulin-antagonist. Glucagon increases hepatic glucose production (enhancing glycogenolysis, gluconeogenesis and protein breakdown). Low glucose levels trigger glucagon production, even from denervated, pancreatic </span><span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">- cells; hence, they must be glucose sensitive.</span> <span lang="EN-US">An increased catecholamine secretion from sympathetic nerve endings (NA) and Ad from the adrenal medulla (elicited from the hypothalamic glucostat via the sympathetic nervous system) helps within minutes to compensate, as catecholamines stimulate glycogenolysis, increase lipolysis and inhibit peripheral glucose uptake. Hours later, cortisol and GH also contribute. An appropriate rise of plasma [cortisol] in response to insulin-induced hyperglycaemia documents an intact CRH-ACTH-adrenal axis, and this is the most widely used stress test.</span> <span lang="EN-US">Adrenergic effects, such as trembling fingers, tachycardia, and muscular stiffness warn the hypoglycaemic patient. The glucose consumption by the heart and brain continues. The lack of glucose in the brain makes the patient uneasy at first; he is then inse&shy;cure, anxious and has cold sweat. Later in hypoglycaemia, the patient becomes confused, furious and denies with slurred speech to take glucose.</span> <span lang="EN-US">Blood [glucose] below 2.5 mM elicits hypoglycaemic shock with loss of consciousness (somnolence, sopor or coma), universal cramps and respiratory stop ([[Image:fysiologi_paulev_27-5.jpg]] Fig. 27-5]).<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">Intravenous injection of glucose (50%) is the rational therapy for hypoglycaemic coma. The patients wake up almost immediately, and are then often in a hyperglycaemic state.</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-5.jpg]] Fig. 27-5]<nowiki>: Consequences of hypoglycaemic shock.</nowiki></span>''' <span lang="EN-US">The </span><span lang="EN-US" style="font-family: Symbol">b</span><span lang="EN-US">-cell defects are insufficiently described. Type 2 diabetics do not produce sufficient levels of ATP in the pancreatic </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cells to completely block the K⁺ -ATP channels ([[Image:fysiologi_paulev_27-2.jpg]] Fig. 27-2]). Thus, the </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell does not hypopolarize adequately in response to hyperglycaemia. Therefore, the voltage dependent Ca²⁺ -channels is insufficiently activated, and intracellular [Ca²⁺] do not increase enough to trigger the insulin exocytosis needed. Sulfonylurea compounds close the K⁺-ATP-channels and thus help to treat type 2 diabetes.</span> <span lang="EN-US">'''4. Oral and intravenous glucose tolerance tests'''</span> <span lang="EN-US">The test is performed orally or intravenously.</span> ''<span lang="EN-US">Oral test.</span>''<span lang="EN-US"> The patient drinks a glucose solution containing 75 g glucose within four minutes (WHO). The blood concentration in venous plasma ([glucose]) is followed over 3 hours by blood sampling.</span> <span lang="EN-US">Normal individuals start from a low fasting [glucose]<span style="mso-spacerun: yes"> </span>such as 5.5 mM or less. The blood [glucose] peaks after one hour and ''returns to normal within two hours ''(less than 6.7 mM in Fig. 27-5). Persons with ''impaired glucose tolerance'' start with a fasting level less than 7.8 mM, and after 2 hours the level is 7.8-11.1 mM.</span> <span lang="EN-US">'''[[Image:fysiologi_paulev_27-5.jpg]] Fig. 27-5]<nowiki>: Oral glucose tolerance curves for a normal person, a diabetic, a patient with hyperthyroidism and a patient with myxoedema.</nowiki>'''</span> <span lang="EN-US">The ''diabetic patient'' typically starts from a high fasting [glucose], such as values above 7.8 mM, and increase to a very high level. The blood [glucose] is not back to normal within two hours, but stays above 11.1 mM. This test pattern is the clinical WHO criterion of diabetes (Fig. 27-5).</span> <span lang="EN-US">A patient with hyperthyroidism (Graves disease or Morbus Basedowii) has a rapid intestinal absorption and a rapid combustion of glucose. The myxoedematous patient has a slow absorption and a slow combustion of glucose.</span> '''<span lang="EN-US">[[Image:fysiologi_paulev_27-6.jpg]] Fig. 27-6]<nowiki>: Results of i.v. glucose tolerance tests from a normal person and from a diabetic.</nowiki></span>''' ''<span lang="EN-US">Intravenous (i.v.) test.</span>'''''<span lang="EN-US"> </span>'''<span lang="EN-US">We inject 25 g glucose intravenously over a period of 4 minutes. We then measure the blood [glucose] every 10 min for at least an hour in order to determine the half-life from a semi-logarithmic plot (Fig. 27-6). The metabolic combustion rate for glucose is exponential, so it is easy to calculate the metabolic rate constant (k) expressed in percentages.</span> <span lang="EN-US">Note that the ''metabolic rate constant k ''here is the amount of glucose combusted divided by the total amount of glucose in a mainly extracellular distribution volume. The half-life (T_1/2) is equal to 0.693/k.<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">All glucose combustion rates ''above 1.2% per min ''are normal.</span> <span lang="EN-US">'''[[Image:fysiologi_paulev_27-7.jpg]] Fig. 27-7]<nowiki>: Intravenous Glucose Tolerance Test</nowiki>'''</span> <span lang="EN-US">'''5. Treatment of diabetes mellitus'''</span> <span lang="EN-US">A normal person with three meals per day will have ''three ''peak concentrations of glucose and insulin in his blood. It is possible to obtain such a time profile in a diabetic person by the following strategy. Inject a fast&#x2011;acting insulin three times a day just before meals and a slow&#x2011;acting insulin at night. This is the ''physiologic ''principle. The aim of this procedure is to reduce the number of acute and chronic complications for diabetics.</span> <span lang="EN-US">All diabetics are recommended to eat healthy just like anyone else. When diet alone is insufficient to achieve a satisfactory blood glucose, a slim type II diabetic is treated with sulphonylurea compounds. The obese type II diabetic is treated with a biguanide called metformin. Patients, who have been in metabolic acidosis, are usually treated best with insulin.</span> <span lang="EN-US">'''6. Summary of the diabetic condition'''</span> <span lang="EN-US">A poorly controlled diabetic condition leads to extracellular hyperglycaemia, glucosuria, metabolic acidosis, polyuria (osmotic diuresis), dehydration and polydipsia. The osmotic diuresis leads to the excretion of Na⁺ and water, which results in Na⁺ and ECV depletion.</span> <span lang="EN-US">Intracellular lack of glucose activates glycogenolysis in the liver and muscles, and accelerates muscular proteolysis and lipolysis. This liberates free fatty acids, which are converted to ketone bodies.</span> <span lang="EN-US">A patient with hyperglycaemia above 25 mM loses consciousness to such a degree that contact is impossible (ie, coma).</span> <span lang="EN-US">The increased rate of cholesterol production increases the occurrence of atherosclerosis and of diabetic nephropathy. Albuminuria, hypertension and low GFR characterise diabetic nephropathy.<span style="mso-spacerun: yes"> </span></span> ''<span lang="EN-US">'''Self-Assessment'''</span>'' '''<span lang="EN-US">[http://www.mfi.ku.dk/ppaulev/chapter27/answer27.htm#Multiple%20Choice%20Questions Multiple Choice Questions]</span>''' '''<span lang="EN-US">I</span>'''<span lang="EN-US">. '''Each of the following five statements have True/False options'''<nowiki>:</nowiki></span> <span lang="EN-US">A. <span style="mso-tab-count:1"> </span>Peptides and protein hormones are lipophobic.</span> <span lang="EN-US">B. <span style="mso-tab-count:1"> </span>Infertility is a diagnosis used on a couple, which have been unable to conceive<span style="mso-spacerun: yes"> </span>during one year of unprotected intercourse.</span> <span lang="EN-US">C. <span style="mso-tab-count:1"> </span>Chronic hypoadrenalism is also called Addison&rsquo;s disease.</span> <span lang="EN-US">D.<span style="mso-tab-count:1"> </span>Nephrogenic diabetes insipidus, is a condition where the renal cells are resistant to ADH.</span> <span lang="EN-US">E. <span style="mso-tab-count:1"> </span>Glycerol and lactate are substrates for hepatic gluconeogenesis.</span> '''<span lang="EN-US">II. Each of the following five statements have True/False options:</span>''' <span lang="EN-US">A.<span style="mso-tab-count:1"> </span>Receptors are frequently glycosylated, so one signal molecule linked to a receptor is always enough to elicit a response.</span> <span lang="EN-US">B. <span style="mso-tab-count:1"> </span>The incidence of atherosclerosis is correlated to the total </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">cholesterol</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US">, the </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">LDL</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US">, and the </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">LDL</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US">/ </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">HDL</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"> ratio in blood plasma.<span style="mso-spacerun: yes"> </span></span> <span lang="EN-US">C. <span style="mso-tab-count:1"> </span>Oestrogens, exercise, nicotinic acid and alcohol increase the plasma-HDL.</span> <span lang="EN-US">D. <span style="mso-tab-count:1"> </span>Omeprazole stimulates the luminal gastric proton-pump.</span> <span lang="EN-US">E. <span style="mso-tab-count:1"> </span>Prostaglandins are primarily paracrine hormones, which act through receptors linked to G-proteins.</span> <span lang="EN-US">'''[http://www.mfi.ku.dk/ppaulev/chapter27/answer27.htm#Case%20History%20A Case History A]'''</span> ''<span lang="EN-US">A 19 year old male, body weight 80 kg,<span style="mso-spacerun: yes"> </span>was suddenly complaining of fever during his work and ordered home to bed. The patient was living alone. Fortunately a colleague visited him the next morning. He had to break the door down and found the patient unconscious. The patient arrived at the hospital in deep coma. A blood sample from the radial artery showed the following results: </span><span lang="EN-US" style="font-family:Symbol">b</span><span lang="EN-US">-cell antibodies, P_aCO</span>_{<span lang="EN-US" style="font-size:7.0pt;mso-bidi-font-size:10.0pt">2</span>}<span lang="EN-US"> 27 mmHg, pH 7.21, actual bicarbonate 10.5 mM, O₂ saturation 0.96 and [glucose] 32 mM (5.75 g/L).<span style="mso-spacerun: yes"> </span>The Base Excess is -15 mM in the extracellular fluid volume (see [http://www.mfi.ku.dk/ppaulev/chapter17/images/17-12.jpg]] Fig. 17-12]).<span style="mso-spacerun: yes"> </span>The urine contained glucose and ketone bodies.</span>'' ''<span lang="EN-US">The patient's breathing was deep and fast, his heart rate was 115 beats/min, and his blood pressure was 90/55 mmHg. The mucous membranes of the mouth were dry and the tonsils were enlarged and infected. The rectal temperature was 39.9 Centigrade.</span>'' ''<span lang="EN-US">1. <span style="mso-tab-count:1"> </span></span>''<span lang="EN-US" style="mso-bidi-font-style:italic">Explain the condition of the patient concerning thermo-balance, carbohydrate metabolism, acid-base balance and fluid balance.</span> <span lang="EN-US" style="mso-bidi-font-style:italic"><span style="mso-spacerun: yes"> </span>2. <span style="mso-tab-count:1"> </span>Describe a rational treatment of the four homeostatic disturbances mentioned<span style="mso-spacerun: yes"> </span>in 1.</span> <span lang="EN-US" style="mso-bidi-font-style:italic"><span style="mso-spacerun: yes"> </span>3. <span style="mso-tab-count:1"> </span>Following eight hours of treatment the blood pH was 7.41 and P_aCO</span>_{<span lang="EN-US" style="font-size:7.0pt;mso-bidi-font-size:10.0pt;mso-bidi-font-style: italic">2</span>}<span lang="EN-US" style="mso-bidi-font-style:italic"> 42 mmHg, but the patient is still hyperventilating. Explain why.</span> <span lang="EN-US" style="mso-bidi-font-style:italic"><span style="mso-spacerun: yes"> </span>4. <span style="mso-tab-count:1"> </span>Following 24 hours of treatment all blood gas values were normal and the patient was resituated. Why did the patient stop to hyperventilate?</span> <span lang="EN-US">'''[http://www.mfi.ku.dk/ppaulev/chapter27/answer27.htm#Case%20History%20B Case History B]'''</span> ''<span lang="EN-US">A female of 49<span style="mso-spacerun: yes"> </span>years and with a height of 1.52 m is in hospital due to obesity and related problems. Her weight is 74 kg. She has developed skin mycoses and multiple boils. In the morning (fasting state) a blood sample shows a blood [glucose] of 7.4 mM, but glucose is not found in the urine. </span>'' ''<span lang="EN-US">At the hospital her total body water is measured following intravenous injection of radioactive water (5.5 </span><span lang="EN-US" style="font-family:Symbol">&times;</span><span lang="EN-US"> 10⁷ Becquerel or Bq tritium water). Her bladder is emptied at the time of injection. Two hours later the bladder is drained for 95 ml of urine with a concentration of 1 598 400 Bq per l. </span>'' ''<span lang="EN-US"> At this time the indicator is evenly distributed in the total body water with a concentration of 1 520 700 Bq per l. The amount of indicator lost in the urine is 2/3 of the total loss. </span>'' ''<span lang="EN-US">1.<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'' <span lang="EN-US" style="mso-bidi-font-style:italic">What is the principle for estimation of total body water?</span> ''<span lang="EN-US">2.<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'' <span lang="EN-US" style="mso-bidi-font-style:italic">Calculate the total body water in litres and in fraction of her body weight.</span> ''<span lang="EN-US">3.<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'' <span lang="EN-US" style="mso-bidi-font-style:italic">Is this a normal result?</span> ''<span lang="EN-US">4.<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'' <span lang="EN-US" style="mso-bidi-font-style:italic">The patient is obese, but is this a serious overweight?</span> ''<span lang="EN-US">5.<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span>'' <span lang="EN-US" style="mso-bidi-font-style:italic">Does she have symptoms and signs of complications? </span> <span lang="EN-US">'''[http://www.mfi.ku.dk/ppaulev/chapter27/answer27.htm#Case%20History%20C Case History C]'''</span> ''<span lang="EN-US">A 23-year old male was saved after 30 days in the ruins of a house following earth quake. There was no food but sufficient water. At the arrival to the hospital the patient was in syncope with frequent, deep respiration, and the expired air smelled of acetone. The skin was dirty with brown pigmentation. The cardiac rate was 85 bpm, and the arterial blood pressure was 11.3/7.3 kPa (85/55 mmHg).</span>'' ''<span lang="EN-US">The blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"><span style="mso-spacerun: yes"> </span>was 2.2 mM, and the plasma </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">FFA</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"> was increased. The serum concentrations of proteins and essential amino acids were reduced. The blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">haemoglobin</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"> was 95 g l^-1. There was moderate antidiuresis with ketonuria with signs of water retention and a high nitrogen loss in the urine.</span>'' ''<span lang="EN-US">The patient was treated with parenteral administration of glucose, amino acids and electrolytes. Following the glucose intake, the blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"><span style="mso-spacerun: yes"> </span>was increased to 10 mM, and glucosuria occurred. A glucose tolerance test was performed and resulted in a high blood </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">[</span><span lang="EN-US">glucose</span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">]</span><span lang="EN-US"> level that had not reached the normal level within 2 hours.</span>'' # <span lang="EN-US" style="mso-bidi-font-style:italic">Describe the energetic events leading to survival.</span> # <span lang="EN-US" style="mso-bidi-font-style:italic">Why did the patient smell of acetone?</span> # <span lang="EN-US" style="mso-bidi-font-style:italic">What happened to the carbohydrate metabolism of the patient?</span> # <span lang="EN-US" style="mso-bidi-font-style:italic">Explain the high nitrogen loss in the urine.</span> <span lang="EN-US" style="mso-bidi-font-style: italic">See [http://www.mfi.ku.dk/ppaulev/chapter27/answer27.htm answers]</span> ''<span lang="EN-US">'''Highlights'''</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Glucose is absorbed through the luminal membrane of the intestinal cells in glucose-Na⁺ transporter proteins. The two substances pass through the basolateral membrane via separate routes: Glucose passes in a special glucose-transporter, and Na⁺ is transferred by the Na⁺-K⁺&#x2011;pump.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Somatotropin &#x2011; human growth hormone (GH) &#x2011; is an insulin-antagonist, but together with insulin probably the most important anabolic hormone.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Glucose sensitive neurons in the hypothalamus (the glucostatic centre) react to hypoglycaemia by releasing glucagon from the pancreatic </span>''''<span lang="EN-US" style="font-family:Symbol">a</span><span lang="EN-US">-cells and catecholamines from the adrenal medulla by action of the sympathetic system. </span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Since the hypophysis hormones ACTH and GH are insulin-antagonists the net effect of the hypophysis, when not balanced by a normal pancreatic insulin secretion, is a reduced glucose tolerance. </span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">The endocrine pancreas or the pancreatic islets are synonyms for the produc&shy;tion site of four polypeptide hormones: Glucagon, insulin, somatostatin, and pancreatic polypeptide (PP). </span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Insulin is synthesized as proinsulin, which is stored in granules close to the cell membrane of the </span><span lang="EN-US" style="mso-char-type: symbol; mso-symbol-font-family: Symbol; font-family: Symbol; mso-ascii-font-family: Times New Roman; mso-hansi-font-family: Times New Roman">b</span><span lang="EN-US">-cells of the pancreatic islets. When the secretory granules release proinsulin to the portal blood and later the extracellular fluid volume, connecting peptide (C-peptide) and two amino acids breaks off.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">A poorly controlled diabetic condition leads to extracellular hyperglycaemia, glucosuria, metabolic acidosis, polyuria (osmotic diuresis), dehydration and polydipsia. The osmotic diuresis leads to the excretion of Na⁺ and water, which results in Na⁺ and ECV depletion. </span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Intracellular lack of glucose activates glycogenolysis in the liver and muscles, and accelerates muscular proteolysis and lipolysis. This liberates free fatty acids, which are converted to ketone bodies.</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">A patient with hyperglycaemia above 25 mM loses consciousness to such a degree that contact is impossible (ie, coma).</span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">The increased rate of cholesterol production increases the occurrence of atherosclerosis and of diabetic nephropathy. </span>'' <span lang="EN-US" style="font-family:Symbol">&middot;<span style="font:7.0pt &quot;Times New Roman&quot;"> </span></span> ''<span lang="EN-US">Albuminuria, hypertension and low glomerular filtration rate characterise diabetic nephropathy.'''<span style="mso-spacerun: yes"> </span>'''</span>'' ''<span lang="EN-US">'''Further Reading'''</span>'' <span lang="EN-US">Almind, K., C. Bj&oslash;rb&aelig;k, H. Vestergaard, T. Hansen, S. Echwald, and O. Pedersen. "Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus." ''The Lancet'' 342: 828-832, 1993.</span> <span lang="EN-US">Ashcroft, F.M. and S.J.H. Ashcroft. "Insulin." ''IRL Press at Oxford Univ''. Press, Oxford 1992.</span> <span lang="EN-US">Banting, F.G. and C. H. Best. "Internal secretion of pancreas." ''J. Lab. and Clin. Med. ''7: 251-326, 1922.</span> <span lang="EN-US">Flatt, P.R. "Nutrient regulation of insulin secretion." ''Portland Press Ltd.'', London 1991.</span> [[Category: Fysiologi]]

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