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glucose homeostasis 2024.pdf
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2024-12-06 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Prof Suzanne L Dickson Glucose Homeostasis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 1 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Topics ØGlucose homeostasis – the physiological challenge ØGlucostatic hormones that decrease blood glucose. • Insulin • Incretins ØGlucostatic hormones that increase blood glucose • Glucagon • Adrenaline • Cortisol • Growth hormone ØOther hormones ØThe clinical context: diabetes mellitus | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 2
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2024-12-06 2 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GLUCOSE (mmol/l) time Clock time Normal range is 4 to 6.5 mmol/L Learn values!! Blood glucose concentration is under tight homeostatic control 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY HIGH BLOOD GLUCOSE IS BAD
- CHRONIC. Persistent high glucose levels leads to many complications as seen in patients with diabetes mellitus (eg fatigue, thirst, retinopathy, kidney failure, diabetic foot etc - see later slides).
- ACUTE high levels can be life threatening due to diuresis (fluid loss). LOW BLOOD GLUCOSE IS BAD –An insufficient glucose supply to the brain will cause coma and death. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Why is it important to control blood glucose? 4
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2024-12-06 3 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON GLUCOSE (mmol/l) Meals time Clock time INSULIN µU/ml time Clock time The most important hormone that reduces blood glucose after meals is INSULIN. Blood insulin levels are determined by both the amount of food we eat and its composition. Meals The physiological challenge: to maintain <6.5 mmol/l no matter what and how much we eat. Glucose homeostasis – the problem of meals INSULIN REDUCES BLOOD GLUCOSE BY MOVING IT INTO CELLS, WHERE IT CAN BE USED AND/OR STORED. 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Oral glucose tolerance test: a diagnostic tool for diabetes § Overnight fast § Oral glucose drink § Measure glucose ² Fasting level ² How large an increase? ² How rapid recovery? § More sensitive than fasting glucose to identify (pre-)diabetes. How well does the body tolerate an acute glucose challenge? Minutes from oral glucose load Glucose concentration (millimoles/litre) DIABETES HEALTHY In healthy individuals blood glucose concentrations are tightly regulated. Fasting normal range: 4-6 mmol/l oral glucose 0 50 100 150 0 2 4 6 8 10 12 14 16 6
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2024-12-06 4 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Diabetes mellitus This girl would have died within days without insulin treatment.
- Blood glucose levels high
- No/very low blood insulin levels
- Blood glucose high
- High insulin levels (but insufficient for need)
- Insulin resistance - tissues cannot take up glucose.
- Commonly associated with obesity TYPE 1 TYPE 2 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin need and insulin production become uncoupled in disease | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Healthy (Normo- glycemia) Type I diabetes (Hyper- glycemia) Insulin Resistance (Normo- glycemia) Type II diabetes (Hyper- glycemia) Insulin need Insulin production 8
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2024-12-06 5 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucose homeostasis – the problem of fasting | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØNormally the brain only uses glucose as its energy source. ØAfter several days fasting, the brain can use ketones (eg acetyl acetate or ß-hydroxybutyrate) as an alternative fuel. BUT, at best, ketones only provide 50% of the brain's energy, the rest must come from glucose. 5 4 Plasma Glucose (mM) Brain Glucose (mM) 3 2 1 0 5 10 15 The physiological challenge is to ensure plasma glucose remains high enough to supply enough glucose to the brain when fasting and between meals. Death occurs when plasma glucose levels fall below 1 mM 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Glucose homeostasis – the problem of fasting How can we maintain >4 mmol/l if we don’t eat? Ø GET GLUCOSE FROM GLYCOGEN STORES IN LIVER (Glycogenolysis). Ø MAKE MORE GLUCOSE. Liver synthesizes glucose from non-carbohydrate carbon substrates (eg lactate, glycerol) and amino acids. (Gluconeogenesis). Ø DON’T LET ORGANS USE GLUCOSE (& KEEP FOR BRAIN INSTEAD). Less glucose uptake by muscle & fat (insulin resistance i.e. unable to respond to insulin). Go to the bank Make more money Stop spending I don’t have any money 11
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2024-12-06 6 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The main glucose-regulating hormones | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Ø INSULIN Ø “INCRETINS” (eg. GLP-1) Ø GLUCAGON Ø ADRENALINE Ø GROWTH HORMONE Ø GLUCOCORTICOIDS In addition, the following hormones have beneficial (good) effects on blood glucose: Ø LEPTIN deficiency during fasting decreases blood glucose – as leptin helps glucose entry to muscle cells. Ø IGF-1 has insulin-like effects to reduce blood glucose. Ø GHRELIN (released in fasting) increases blood glucose, probably by inducing insulin resistance (could be growth hormone-dependent) MAIN HORMONES Decrease blood glucose after meals Increase blood glucose between meals 12 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Topics ØGlucose homeostasis – the physiological challenge ØGlucostatic hormones that decrease blood glucose. • Insulin • Incretins ØGlucostatic hormones that increase blood glucose • Glucagon • Adrenaline • Cortisol • Growth hormone ØOther hormones | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 13
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2024-12-06 7 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin’s functions | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØPrimary target tissues: liver, adipose tissue, and skeletal muscle. ØInsulin’s major function: to facilitate cellular glucose uptake in many tissues (esp muscle and fat but not brain). ØInsulin’s mechanism for glucose homeostasis: § Increases glucose transport into insulin-sensitive cells § Enhances cellular utilization and storage of glucose § Enhances utilization of amino acids § Promotes fat synthesis 14 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin’s functions | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Insulin is released in response to feeding Inhibits lipolysis + glucose glucose fatty acids amino acids + ¯ Glycogenolysis ¯ Gluconeogenesis + +
Insulin transports nutrients to organs where they can be used or stored. It also suppresses breakdown of stores. 15
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
How does glucose get into cells? Glucose transporters
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
• Glucose enters cells by facilitated diffusion, involving glucose transporters
• >14 kinds of glucose transporters in man (GLUT1-GLUT14). GLUT1-4 are best characterized.
Tissue
Function
GLUT1
Fetal tissues, blood-brain
barrier, brain, red blood
cells, colon
Basal glucose uptake by most cells (not neurones).
Glucose uptake into brain
GLUT2
b Cells of islets
(pancreas), liver, kidneys,
etc
Glucose-sensing in pancreas.
Bi-directional glucose flux in liver (uptake glucose for glycolysis,
and release of glucose during gluconeogenesis).
Transport of glucose, galactose and fructose out of intestinal cells
GLUT3
Brain, placenta, kidneys
Basal glucose uptake including nerve cells
GLUT4
Brown & white fat,
skeletal muscle
Insulin- (and exercise)-stimulated glucose uptake.
Note: SGLT2 (sodium glucose cotransporter 2) is involved in glucose reabsorption in the kidney.
IMPORTANT: SGLT2 inhibitors à glucose loss in urine (i.e. new diabetes medication).
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
GLUT4 – important for insulin’s effects
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
ØGlucose uptake (fat & muscle) - determined by number of GLUT4 transporters on cell
surface.
ØInsulin action moves GLUT4-containing intracellular vessicles to the cell surface. Exercise
also does this (an insulin-independent effect).
Insulin
receptor
Phosphoinositide
3-kinase (PI3K)
Glucose transport
FUSION
INTERNALISATION
GLUT4
AKT2
GLUT 4 is the
only insulin-
sensitive
glucose
transporter
17
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2024-12-06 9 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin causes the fusion of GLUT4 containing vessicles with the membrane | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Important: If GLUT4 vesicles do not move to the surface, this can cause type 2 diabetes. Eg AKT2 mutation Adipocyte transfected with a fusion construct of GLUT4 and enhanced green fluorescent protein see Saltiel & Kahn (2001) Nature p. 799 18 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin receptor signalling – some key molecules: IRS-1, PI3-kinase and AKT2 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON • Plasma membrane receptor • Locations: mostly fat, liver & muscle • Belongs to the tyrosine kinase (TK) receptor family • Heterotetramer complex • a subunits – binds ligands and b subunits • b subunits – anchor receptor in membrane and contain TK activity. • A key intracellular signal is insulin receptor substrate 1 (IRS-1). NOTE: It is absolutely NOT a G protein coupled receptor 19
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2024-12-06 10 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin receptor signalling – some key molecules: IRS-1, PI3-kinase and AKT2 | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON AKT2 mutation à One identified cause of type 2 diabetes Important points Ø Insulin receptor activation à IRS1 phosphorylation (amongst others) Ø Phorphorylated IRS-1 binds to proteins that bear a SH2 homology domain, eg PI3K. Ø PI3K recruits Akt2 which is required for GLUT4 to translocate to cell membrane. DNA synthesis Activation of nuclear kinases Phosphorylation of transcription factors Lipid metabolism Amino acid uptake Ion transport Glycogen Synthesis p60 Ras complex Phosphorylation cascade pp90 S6 kinase GLUT4 Containing vessicles pp70 S6 kinase Alternative substrates Other signal GRB2 nck syp sos RAS GAP p62 Shc GRB2 ? AKT2 ? ? ? ? ? ? PI3K Alternative substrates Other signals IRS-1 20 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Where is insulin produced? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON In the Islets of Langerhans in the pancreas – in the beta cells Endocrine portion of pancreas (Islets of Langerhans) Islet of Langerhans. Beta cells (green) produce insulin and alpha cells (red) produce glucagon. The nuclei of the cells is shown in blue. Image of Ge Li/Waterland lab/Environmental Epigenetics,2019. 21
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2024-12-06 11 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Islets of Langerhans - anatomy | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Alpha cells (20%) à glucagon (only site produced) à ghrelin – (but not major site of production) Beta cells (~70%) à insulin (only site produced) à amylin (about 1/100 as much as insulin) Delta cells (<10%) à somatostatin (paracrine role?) PP cells (<5%) à pancreatic polypeptide Epsilon cells (<1%) à ghrelin (very little) Most abundant cell type is the beta cell. These are centrally located. 22 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Insulin biosynthesis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØComprises 2 chains (A and B chains) linked by 2 disulphide bonds. Gly-Ile-Val-Glu-Gin-Cys-Cys-Thr-Ser-Ile-Cys-Ser-Leu-Tyr-Gin-Leu-Glu-Asn-Tyr-Cys-Asn Phe-Val-Asn-Gln-His-Leu-Cys-Gly-Ser-His-Leu-Val-Glu-Ala-Leu-Tyr-Leu-Val-Cys-Gly-Glu-Arg-Gly-Phe-Phe-Tyr-Thr-Pro-Lys-Thr A Chain B Chain S S S S S S Human insulin Ø Preproinsulin (110 aa), proinsulin (86 aa) & insulin (51 aa). Ø Insulin, Proinsulin and C-peptide are co-secreted into blood. Ø Insulin degredation 40-80% as it passes through liver. Folded Pro-insulin C peptide insulin C-peptide 23
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2024-12-06 12 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY C-peptide is a useful diagnostic tool for beta cell function | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØOne molecule of C-peptide is produced for every molecule of insulin. ØC peptide does not have a clear biological role. ØBlood assays for C-peptide enable us to estimate the ability of the pancreas to synthesize insulin. DIAGNOSTIC TOOL: Sometimes you want to know about the ability of a patient’s pancreas to produce insulin. If a patient is receiving insulin injections, how do you know if what you measure is the insulin injected or insulin produced by the pancreas? C-peptide informs on endogenous production but is unaffected by injected insulin. 24 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Food substrates: Glucose is the main controller of insulin secretion. Amino acids and fatty acids also increase release. Hormones: Incretins (eg glucagon-like peptide 1, GLP-1) from enteroendocrine cells in the gut increase release. Adrenaline (from adrenal glands) decreases release. Somatostatin – acts locally in the pancreas (paracrine) to suppress insulin release. Parasympathetic nervous system: The sight, smell and taste of food can increase pancreatic insulin release, engaging the vagus nerve. B-Cell INSULIN 25
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2024-12-06 13 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON B-Cell INSULIN glucose +
- By blood glucose Ø The more glucose is present in the blood, the more will be taken up by the beta cell (involves GLUT2). Ø More glucose inside the beta cell causes more insulin to be released. Important Q: How does the pancreas know to adjust insulin production according to blood glucose levels (ie according to need)? 26 Control of insulin secretion by glucose. Drink glucose solution Drink glucose solution Glucose clamp Plasma glucose (mmol/l) Plasma insulin (mmol/l) Glucose conc Insulin – rate of release Insulin release rate (arbitary units) Insulin release rate (arbitary units) Insulin – rate of release Time (min) Time (min) Time (min) Glucose conc (mM) INSULIN GLUCAGON 27
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Release of stored
insulin
Release of newly
synthesized insulin
Note: This is insulin
release RATE
Important Q: How does the pancreas know to adjust
insulin production according to blood glucose levels (ie
according to need)?
Clamp blood glucose at a high level
Control of insulin secretion by glucose
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Regulation of insulin secretion from the beta cells by
glucose (involves GLUT2)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Glut 2 – large quantity of low affinity
glucose transporters.
Blood glucose concentration controls the
rate of glucose transport into the beta cell.
Glucokinase (glucoseàglucose-6-P). Rate
limiting step for for glucose uptake.
glucose oxidation (glycolysis)
à ATP/ADP
à K+ channel closes
à K+ à depolarization
à opening of VSCC
à Ca2+ entry
à insulin release
GLUT 2
glucose
Glucose-6-P
glucokinase
Metabolism
ATP/ADP
¯K+
ATP-senstive
potassium
channels
close
depol
Voltage -sensitive
Ca channels open
Ca2+
insulin
K+
Note: Sulfonylurea close ATP-sensitive K
channels à Treatment for type 2 diabetes
Beta cell
29
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2024-12-06 15 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Beta cells respond to an increase in extracellular glucose by depolarizing | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Nature 1968 Glucose 6.5 mmol/l Voltage (mV) Glucose 10.0 mmol/l The membrane potential (V) of a single beta cell within an intact pancreas islet recorded in the presence of 6.5 and 10.0 mM glucose as indicated by the staircase. 0 -20 -40 -60 50 s 30 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Amino acids + B-Cell INSULIN glucose + 2. By amino acids Unlike glucose, amino acids do not enter the beta cell by facilitated diffusion. Amino acids have dedicated transporters. 31
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Regulation of insulin secretion by amino acids
Amino acid entry
à ionic changes
à depolarization
à Ca2+ uptake
à exocytosis.
Involves transporters
(i)
symporter for Ala, Gly
& Na+.
(ii)
arginine transport
protein
depol
Voltage -sensitive
Ca channels open
Ca2+
insulin
Beta cell
Alanine
Glycine
Na+
Arginine+
Na+ entry depolarizes cell.
Arginine+ also depolarizes cell.
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UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY
Control of insulin secretion
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
Amino
acids
+
B-Cell
INSULIN
glucose
+
3. By the parasympathetic system
+
Parasympathetic
system
33
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2024-12-06 17 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion by the parasympathetic system | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØSight/taste/smell à ØActivation of vagal reflexes à ØInsulin secretion before food enters gut. ØEarly insulin release helps prepare for the incoming glucose – prevents massive increase in glucose after meals. ØIt can be detected (see graph). In the absence of absorbed glucose early insulin release may even cause a small dip in blood glucose. Subjects have fasted before experiment. Blood glucose (mM/l) 0 5 10 15 20 -5 min 4 8 Insulin already being released before glucose absorbed 34 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Amino acids + B-Cell INSULIN glucose + 4. By incretins + Parasympathetic system incretins + 35
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2024-12-06 18 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Incretins | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØPeptide hormones secreted into blood by enteroendocrine cells in the G-I tract ØExamples: • GLP-1: Glucagon-like peptide 1 • GIP: gastric inhibitory peptide (or glucose- dependent insulinotropic polypeptide) L cells (GLP-1) K cells (GIP) ØMAIN ROLES: insulin secretion, both in preparation for food being absorbed after eating. ØAdditional roles: • slow rate of nutrient absorption by reducing gastric emptying. • directly reduce food intake (CNS). • GLP-1 (BUT NOT GIP) inhibit glucagon release. Food ingestion •GLP-1: Decreases glucagon secretion when glucose high but not when low. Helps avoid hyperglycemia. •GIP: Stimulating glucagon release when glucose levels are low but not when high. Helps avoid 36 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY The presence of food in the gut triggers insulin secretion via incretin release | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØEnteroendocrine cells respond to the presence of food in the gut (starting even before absorption) by releasing incretins. ØIncretins stimulate insulin secretion after eating but also before food is absorbed. ØThus, they help prepare for the incoming glucose load. Subjects have fasted before experiment. Blood glucose (mM/l) 0 5 10 15 20 -5 min 4 8 Insulin already being released before glucose absorbed 37
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2024-12-06 19 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon-like peptide 1 (GLP-1) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØSynthesized by entero-endocrine L cells and in the brainstem. ØReleased when food present in gut. ØDecreases blood glucose (incretin effect) ØVery short half-life in blood (approx. 2 minutes) ØStimulates insulin secretion (& inhibit glucagon release). 38 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Why are incretins important? In normal physiology … • Thanks to incretins, a little insulin is released into the blood even before glucose in the food is absorbed. Without incretin-induced insulin release, the body would not be prepared for the incoming glucose and it could suddenly become very high, which can be dangerous. • In the presence of incretins, much more insulin is released in response to a meal. This is called the “incretin effect”. In T2DM patients … Drugs based on the incretin system have been developed • Long acting GLP-1 analogues (eg exenatide, semaglutide (Ozempic®) • Enzyme inhibitors - that inhibit the enzyme that breaks down GLP-1, thereby increasing circulating GLP-1 levels. 39
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2024-12-06 20 Insulin Glucose Glucose The Incretin Effect Glucose i.v. Insulin Oral Oral i.v. GLP-1, GIP + hh Insulin Incretin Effect Nauck et al 1986 Diabetologia. 1986 Jan;29(1):46-52. Oral glucose makes contact with GI tract and triggers incretin secretion à more insulin secreted after an oral glucose load than after i.v. infusion. This difference = incretin effect
- Experimentally match i.v. glucose to that caused by a glucose infusion
- Measure blood insulin 40 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY GLP-1 system à new drugs for diabetes (and obesity) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON à GLP-1 long acting agonists (eg Exenatide) à DPP-4 inhibitors (DPP-4 = enzyme inactives both GLP-1 & GIP). Mechanism: Prevents GLP- 1 breakdown & prolongs GLP-1 half-life. 41
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2024-12-06 21 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Data from Zander M, et al. Lancet 2002; 359:824-830 Mean Change (%) in Weight From Baseline Mean (SE) r Weight (%) -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 Saline GLP-1 0 2 3 4 5 6 Time (wk) Effect of 6-Week Continuous GLP-1 infusion on Mean Body Weight Incretin-based drugs are new treatments for type 2 diabetes (and cause weight loss) 42 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Topics ØGlucose homeostasis – the physiological challenge ØGlucostatic hormones that decrease blood glucose. • Insulin • Incretins ØGlucostatic hormones that increase blood glucose • Glucagon • Adrenaline • Cortisol • Growth hormone ØOther hormones | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 43
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2024-12-06 22 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Blood glucose mmol/l Result
8 Exceeds renal threshold for uptake of glucose from pre-urine, diuresis (loss of glucose, water*, Na+ and K+ in urine) 5.5 Insulin secretion increases 4.6 Insulin secretion decreases 3.8 Increased secretion of glucagon, adrenaline and growth hormone 3.2 Cortisol secretion 2.8 Confusion 1.7 Weak, sweat, nauseous 1.1 Muscle cramps 0.6 Brain damage, death *Acute fluid loss can become a medical emergency Consequences of hyper- & hypoglycemia (i.e. too high and too low glucose) • | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 44 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon, adrenaline, growth hormone promote glycogenolysis & gluconeogenesis. Glucocorticoids break down muscle (à amino acids for gluconeogenesis). Glucose Production (liver) Blood Glucose Glucose Consumption (Muscle and adipose tissue) insulin _
- (muscle breakdown) _ glucocorticoids glucagon Adrenaline & noradrenaline Growth hormone
_ Key glucostatic hormones- divergent roles • | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 45
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2024-12-06 23 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Synergistic effects of anti-insulin hormones to increase blood glucose | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Cortisol has a “permissive role” Permissive: allows a biological or biochemical process to occur 46 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØWhere produced? Peptide hormone, produced by alpha cells in the Islets of Langerhans of the pancreas 47
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2024-12-06 24 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØWhere produced? Peptide hormone, produced by alpha cells in the Islets of Langerhans of the pancreas ØWhat stimulates & inhibits release? CCK=cholecystokinin 48 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØWhere produced? Peptide hormone, produced by alpha cells in the Islets of Langerhans of the pancreas ØWhat stimulates & inhibits release? ØPrimary actions: increase blood glucose by increasing glycogen breakdown and gluconeogenesis in the liver glucose + Glycogenolysis ¯ Glycogen synthesis Gluconeogenesis + amino acids Important during initial stages of fasting 49
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2024-12-06 25 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucagon | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON ØWhere produced? Peptide hormone, produced by alpha cells in the Islets of Langerhans of the pancreas ØWhat stimulates & inhibits release? ØPrimary actions: increase blood glucose by increasing glycogen breakdown and gluconeogenesis in the liver. ØThe glucagon receptor is a G protein-coupled receptor. ØA life-saving safe injectable treatment for hypoglycemia. 50 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY ØThink of glucagon as the main hormone acting in the opposite way to insulin. It is important inbetween meals, helping to keep glucose levels up, by enhacing glycogen breakdown and gluconeogenesis. ØIf you eat a diet low in carbs (eg LCHF – low carb high fat diet), you need to mobilize glucose from stores and generate new glucose. The substrates for gluconeogenesis are free fatty acids (from fat breakdown) and amino acids (from protein breakdown). Glucagon 51
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2024-12-06 26 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 52 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Effect of high carbohydrate and high protein meal on hormone secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Protein meal (ie high amino acids) mg% pg/ml Plasma Concentration µU/ml GLUCOSE INSULIN GLUCAGON mg% pg/ml µU/ml meal GLUCOSE INSULIN GLUCAGON aaminonitrogen minutes meal Carbohydrate meal (ie high glucose) Both meals stimulate insulin release. Amino acids also stimulate glucagon release, which saves B-glucose levels from falling if carbs are low 53
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2024-12-06 27 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Control of insulin secretion | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Amino acids + B-Cell INSULIN glucose + 2. By amino acids Although amino acids increase insulin secretion (which lowers blood glucose by increasing glucose uptake to fat and muscle), they also stimulate glucagon release (which promotes glycogenolysis and gluconeogenesis i.e. release and production of new glucose). blood glucose
A-Cell GLUCAGON + glycogenolysis gluconeogenesis (via increased glucose uptake in muscle & fat) 54 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Pro-glucagon | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Thus, although proglucagon can be found in many tissues, glucagon is only released from the alpha cells. 55
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2024-12-06 28 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Fear- fright – flight. Need energy (glucose) fast A role for adrenaline 56 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Adrenaline’s effects on glucose homeostasis | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Glycogenolysis, lipolysis Important during acute stress (minutes) eg exercise free fatty acids á glucose + á Glycogenolysis á Glycogenolysis Lactic acid á Gluconeogenesis 57
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2024-12-06 29 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY During acute stress adrenaline increases blood glucose | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Central Nervous System Splanchnic nerves (+) Liver (+) (+) (-) Hypoglycaemia Glucose Glucagon adrenaline a islets Adrenal medulla Adrenaline
- in liver, it causes glycogenolysis (& gluconeogenesis to a lesser extent)
- It also stimulates glucagon release from the pancreas. Stress from eg fear-flight-flight, hypoglycemia and cold exposure 58 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucocorticoids (from adrenal cortex) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON Important during long term/repeated stress and starvation
Ketone bodies á Glycogen synthesis + Subcutaneous fat “slow” Visceral fat “fast” free fatty acids amino acids glucose + á Gluconeogenesis + Insulin resistance Protein catabolism, glycogenesis, gluconeogenesis, ketogenesis, decreased glucose utilization 59
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Cortisol deficiency (eg Addison’s disease)
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
ØBlood glucose normal as long as food intake is maintained.
ØFasting/starvation is life-threatening due to risk of
hypoglycaemia
ØGlycogen stores in liver and muscle become depleted.
ØBecomes difficult to use other sources of stored energy eg
protein & triglycerides.
JF Kennedy – probably the most famous person to
suffer from this disease
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Cortisol excess – Cushings disease
ØGlucose tolerance* reduced by 80% - they have high
blood glucose levels.
Ø20% patients have type 2 diabetes.
ØGlucocorticoids are required for glucagon to exert its
gluconeogenic effect during fasting (permissive role).
*Impaired glucose tolerance (IGT) is a pre-diabetic state
of hyperglycemia that is associated with insulin resistance
and increased risk of cardiovascular pathology.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
61
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2024-12-06 31 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Growth hormone (GH) ØProduced by the somatotrophs of the anterior pituitary. ØRelease controlled by the hypothalamus, by negative feedback (via GH and IGF-1) and by ghrelin. ØPlasma membrane receptor. Dimerization. ØActions: growth (anabolic) and metabolism (lipolytic, diabetogenic). Metabolic actions important when fasting or when blood glucose levels fall. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 62 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Growth hormone (GH) is diabetogenic, lipolytic (and anabolic) Important when using fat rather than carbohydrate as an energy source (eg fasting). | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON free fatty acids glucose Gluconeogenesis amino acids (Not during fasting) 63
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2024-12-06 32 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Metabolic profile of the GH-deficient patient Ø central adiposity (apple-shaped) ØInsulin resistance (maybe secondary to the central adiposity). ØLiver: ¯ glycogen stores, ¯ gluconeogenesis ØLipid profile: triglycerides, LDL- cholesterol, ¯ HDL-cholesterol, apolipoprotein b (promotes CV disease and arterosclerosis). | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 64 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Metabolic profile of a patient with acromegaly ØInsulin resistance, ØGH blocks insulin’s actions (inhibits phosphorylation of the insulin receptor and IRS-1) ØMobilization of free fatty acids leading to further worsening of insulin resistance. ØAbnormalities overcome by either lowering of GH secretion or by blocking GH action. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 65
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2024-12-06 33 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Acetyl CoA b-oxidation (liver) Gluconeogenesis Glycogenolysis Amino acids glycerol Glucose ketones Cortisol GH Adrenaline Glucagon Cortisol Glycogen synthesis Glucagon, GH, cortisol Cortisol Summary of anti-insulin hormone action (eg in fasting) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON FFA 66 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Topics ØGlucose homeostasis – the physiological challenge ØGlucostatic hormones that decrease blood glucose. • Insulin • Incretins ØGlucostatic hormones that increase blood glucose • Glucagon • Adrenaline • Cortisol • Growth hormone ØOther hormones | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 67
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2024-12-06 34 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Leptin – beneficial effects to lower blood glucose | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 68 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ghrelin – improves (raises) blood glucose when fasting | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 69
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DIABETES MELLITUS: Topics
Contect from Anders Rosengren
Type 1, Type 1.5, Type 2 & gestational diabetes
Symptoms and Diagnosis
Insulin resistance and carbohydrate metabolism in
diabetes.
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Why is diabetes mellitus an important disease?
• Increases the most amongst all diseases!
Current worldwide: 463 million, 50% 20-60 years old
By 2035: 592 million worldwide
Current Sweden: 4.8% of the population
• A worldwide pandemic
The increase in type 2 diabetes mellitus (T2DM): ”diabetes-causing
lifestyle”
• Developing countries – those affected even younger
50% type 2 diabetes occurs in those aged 40-59
T2DM is even the most common form in adolescents.
Contect from Anders Rosengren
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
71
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2024-12-06 36 2014 2035 WORLD 387 million WORLD 592 million people living with diabetes Middle East and North Africa 85% South East Asia 64% South and Central America 55% Western Pacific 46% North America and Caribbean 30% Europe 33% Africa 93% 53% Contect from Anders Rosengren 72 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Most common. 90-95% all diabetes 73
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2024-12-06 37 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Kalle 12 years old • Previously healthy • Recent weeks - tired • Very thirsty Polydipsi (↑ urine) • Frequent urination
Polyuria – osmotic diuresis • Very tired (+ mucous membranes • Acetone smell • B-glucose: 22 mmol/l • Urine teststick: ↑ glucose (fungal infections, genital itching) ↑ ketones • Stomach pain/vomiting (ketoacidosis, hyperosmolar hyperglycaemic syndrome) • Serum insulin: 0 ng/mL C-peptide: 0 nmol/L • Previously normal vision but now sits 1 metre in front of TV Myopathy – eye swells (osmotic effect of glucose) • Lost 3 kg in weight during 2 weeks (insulin deficiency à ↑ lipolysis & ↓ lipogenesis) | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 74 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucose metabolism in diabetes Glucose Glycogenolys Glukoneogenes Heart Red blood cells Kidneys Adipose tissue Musculature Brain Liver Glycerol FFA Insulin 0 Lactate Alanin Contect from Anders Rosengren | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 75
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2024-12-06 38 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Even type 1 diabetes mellitus (T1DM) is increasing • 10% of all diabetes is type 1. • T1DM increasingly common. Almost 30% ↑↑ over past 30 years. Number of sick children with T2DM aged 0-14 has ↑↑ by 3% every year since 1980. • There is a clear tendency for T1DM to affect younger children. It is not uncommon for 1-2 year olds to become ill. • Just over 1% of all children born in Sweden have T1DM (about 700 children and adolescents develop the disease each year) • Around 98,000 children are affected by T1DM each year in the world Contect from Anders Rosengren | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 76 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Type 1 diabetes mellitus (T1DM) • Insulin-producing β-cells destroyed due to auto-antibodies. • 90% T1DM have auto-antibodies: directed against substances in the beta cells: insulin, GAD (glutamic acid decarboxylase) and IA-2 (tyrosine phosphatase). • Theory: a certain type of gene + triggering factor is required (e.g. viruses, chemicals or other environmental factors). • 60% of the hereditary risk of T1DM is in the HLA (human leucocyte antigen) system (that labels cells as belong to the body or to be rejected). • Risk genes are common in the population (about 20%) but only 7% (of this 20%) get T1DM. • Autoimmune disease? – Limited evidence for this. Inhibition of T-cell mediated autoimmunity in newly infected patients has failed. • Inflammatory disease affecting the entire pancreas, most important clinical symptoms come from the loss of insulin producing cells. Contect from Anders Rosengren | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 77
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2024-12-06 39 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Ove, 58 år • Fatigue, dizziness, depression • Mother with diabetes • Weight 126 kg • Waist circumference 103 cm • BMI 33 kg/m2 • Blood pressure 185/100 • Heart, lungs, abdomen – no problem. • Wound infection knee • B-glucose: 12 mmol/l • Urine teststick glucose: ++ • Ketones: negative • Serum insulin (ref. 68-245 ng/mL) 345 ng/mL • LDL-cholesterol ↑ • HDL-cholesterol ↓ • High triglycerides ↑ Contect from Anders Rosengren | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 78 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Glucose metabolism with diabetes Glucose Glycogenolysis Gluconeogenesis Heart Red blood cells. Kidney Musculature Brain Liver Glycerol FFA Insulin Lactate Alanine Contect from Anders Rosengren Glucotoxicity Lipotoxicity | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 79
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Glucotoxicity (High blood glucose toxic)
à ↓ ability of β-cells to release enough insulin,
à ↓ ability of peripheral target cells' to respond to insulin.
àà a vicious cycle that accelerates hyperglycemia.
Lipotoxicity (High lipid levels toxic)
β-cell damaged. ↓ insulin release.
Peripheral target cells, e.g. vascular endothelium, muscle
and liver cells: impaired function and ↓ insulin sensitivity.
Can be counteracted by metabolic control mainly diet and
exercise but also lipid-lowering pharmacological treatment.
Contect from Anders Rosengren
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
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Type 2 Diabetes Mellitus (T2DM)
• Insulin resistance and insulin deficiency
• Heterogenous illness with many different potential causes
– 80% patients are overweight/obese (BMI > 30 kg/m2)
– Insulin resistance increases with increasing obesity and
abdominal obesity
• Clear association between physical inactivity and
increased risk of T2DM.
Contect from Anders Rosengren
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
81
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Genes and environment work together
• T2DM highly hereditary. If a parent has T2DM, the children have a 40%
risk. They have a 70% risk of falling ill during their lifetime.
• Heredity in T2DM complicated - difficult to identify risk genes.
Polygenetic inheritance (GWAS> 120 loci strongly linked but explains
only 20% of the disease). "A genetic nightmare"!
• Genetics (several genes in collaboration) + lifestyle contribute to the risk
of developing the disease
Contect from Anders Rosengren
| INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON
82
Insulin resistance + Insulin need è T2DM
Insulin need
B-Glucose
Insulin secretion
“Healthy”
Insulin
Resistance.
T2D “β cell loss”.
Not reversible
Reversible
~ 7 yr
0-15yr
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2024-12-06 42 Type I DM Type 2 DM Lean or over weight Overweight ~ 80% Ketosis inclined No ketosis Symptoms for weeks before diagnosis Symptoms for months before diagnosis Age onset <40 år Age onset typically >40 år Heredity 10 % Heredity common HLA antigens precede disease in 90-95 % cases HLA antigens precede disease in 60 % cases (as in normal population) Islet cell antibodies at onset positive in about 70-80 % cases Islet cell antibodies at onset - negative Clinical characteristics of type 1 and type 2 diabetes 84 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Gunilla 37 years old • Presented as sweating and frequent urination • 28th week of gestation • Heredity: Mother with DM • B-glucose: 12 mmol / l • Urine test stick glucose: +++ • Ketones: 0 • U-Nitrite: + • Serum insulin (ref. 68- 245 ng / mL) 675 ng / mL Referral to a diabetes nurse and nutritionist 85
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2024-12-06 43 0.8–4.3% of all pregnancies in Sweden Women with GDM are a heterogeneous group (with varying degrees of deviation in glucose tolerance) that developed T2DM Insulin resistance is more pronounced than in a normal pregnancy, and cannot be entirely explained by co-occurring obesity The main cause is a defective insulin response that cannot keep up with increasing insulin resistance during pregnancy GDM usually runs asymptomatically, requiring screening Gestational diabetes Mellitus GDM Defined as pathological glucose tolerance detected during pregnancy. After termination of pregnancy, the glucose metabolic disorder is usually normalized. If not, "reclassification" to type 1 or type 2 diabetes occurs 86 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Fredrik 37 years old • Presented with frequent urination. Prostate? • 70 kg BMI 23 kg/m2 • Blood pressure, heart, lungs, abdomen – no problem. • B-glucose: 13 mmol/l • Blood fats u.a. • Urine teststick glucose: +++ ketones: 0 • Serum insulin (ref. 68-245 ng/mL) 130 ng/mL Metformin Lifestyle advice Referral to diabetes nurse and dietician Type 2 diabetes? | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 87
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2024-12-06 44 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY Fredrik 8 months later Type 1 diabetes? • Tired & frquent urinating • Acetone smell • 66 kg • Blood pressure, heart, lungs, abdomen – no problem. • B-glucose: 17 mmol/l • Urine teststick glucose: +++ • Ketones: +++ • Serum insulin: 0 ng/mL • C-peptid: 0 nmol/L • Islet cell antibodies (GAD) positive | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 88 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY LADA (Latent Autoimmune Diabetes in Adults) between type 1 & type 2 diabetes - type 1.5 diabetes • An autoimmune disease with islet cell antibodies (cf. T1DM) but usually older at the onset of illness. The disease course is slower and milder with preserved insulin production for an extended period of time. Similar in time to the debut of T2DM. • require insulin treatment sooner or later. Important with proper diagnosis in the beginning so that insulin needs are met a.s.a.p. and not delayed. • About 10% of all people with diabetes after the age of 35 have LADA (ie almost as common as T1DM) • LADA was first described at the beginning of the1980s. | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 89
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2024-12-06 45 UNIVERSITY OF GOTHENBURG | SAHLGRENSKA ACADEMY • Diabetes is a worldwide pandemic and the problem is increasing. • Type 1 and Type 2 are the most common forms • The impact of carbohydrate metabolism is insulin deficience and insulin resistance • Insufficient insulin secretion relative to insulin need à Type 2 DM Summary Diabetes | INST. NEUROSCIENCE & PHYSIOLOGY | SUZANNE L DICKSON 90