Diabetes 🍬 Flashcards

Question

Effects of insulin

Answer 1

more glucose channels are inserted into the cell surface membrane, so that more glucose can enter the cell glucose inside the cell is polymerised into glycogen by a process known as glycogenesis (happens in the liver) more glucose is converted into fats, and more glucose is respired

Answer 2

Caused by an absolute insulin deficiency, usually resulting from autoimmune destruction of the insulin-producing beta cells in the pancreas Genetic factors Environmental factors: can trigger the development of autoimmunity to the pancreatic beta cells diet, vitamin D exposure, obesity, early-life exposure to viruses associated with islet inflammation (such as enteroviruses), and decreased gut-microbiome diversity.

Answer 3

Symptoms of diabetes - polyuria, abnormal thirst, unexplained weight loss PLUS one of the following • Serum glucose level ≥ 11.1 mol/I taken randomly, or • Serum glucose level > 7 mmol/I for fasting patients, or • Serum glucose level ≥ 11.1 mol/I two hours after a glucose tolerance test • When no symptoms present, at least two serum glucose measurements made on different days must be within diabetic range for confirmation of diagnosis • Random levels of 5.6-11.1 mol/I may indicate pre-diabetic state of reduced glucose tolerance (need glucose tolerance test - fast overnight, ingest 75 glucose drink next day in morning, then take levels) • Don't use dipstick test to diagnose - when plasma glucose exceeds renal threshold (around 10 mol/l), glucose appears in urine, glycosuria

Answer 4

• Microvascular -damage to small blood cells caused by hyperglycemia (kidney / eyes/ nerves) ! Nephropathy • diabetic kidney disease > caused by damage to small blood vessels in kidney (compromised filtration and then protein in urine) Tested with urine during their annual / 6 month review: ACR test > Tests any protein in urine (bad) . > increases risk of CVD, made worse by high blood pressure. ! Retinopathy diabetic retinopathy caused by small blood vessel damage to retina > leads to progressive loss of vision & possible blindness. ! Neuropathy (ends of fingers and toes loose sensation) > don’t feel pain > infected wound > can cause amputation • diabetes causes nerve damage through different mechanisms, including direct damage by the hyperglycemia and decreased blood flow to nerves by damaging small blood vessels • painful neuropathy does not respond to conventional analgesia • diabetic foot problems can also occur - ulceration and limb amputations • autonomic neuropathy (late stage), neurons of autonomic nervous systems damaged due to chronic hyperglycaemia - sweating, postural hypotension, gastroparesis, diarrhoea, also heart, bladder and sexual function affected

Answer 5

• Macrovascular - damage due to large blood vessels caused by hyperglycaemia • Coronary arteries - development of atheroscelerosis, increased risk CVD (myocardial infarction, heart failure, stroke, peripheral arterial disease) Normally after eating, insulin induces lipase which breaks down fat particles which are then absorbed into fat cells and recombined into triglycerides and stored When no insulin present, fats stay in circulation and are not stored = hyperlipidaemia happens which leads to fat depositing in arterial walls - atherosclerosis > heart attack due to blockage

Answer 6

• Diabetic ketoacidosis, DKA, 'high BG+ketones+acidosis - Happens gradually over days - Insulin deficiency - increase in counter regulatory hormone production (glucagon, cortisol, growth hormone and catecholamines) -enhances hepatic glycogenolysis (glycogen breaks down in liver to make new glucose) and gluconeogenesis (glucose made from other substrates) - hyperglycaemia Enhanced lipolysis (as glucose not being used) - larger amounts of serum fatty acids are metabolized as alternative energy source (ketogenesis) -> accumulation of ketones -> metabolic acidosis - Patient hyperventilates to correct acidosis, acetone breath (pear drops) - Vomiting - dehydration plus decreased pH - coma, medical emergency Hyperosmolar non-ketotic hyperglycaemia, HONK, 'high BG+dehydrated+no ketones' • Happens gradually over days • Blood glucose generally >40 mmol/| • Hypoglycaemia - Adverse effect of insulin treatment (newly diagnosed may pump too much insulin), blood glucose levels less than 3.5 mmol/l - Severe hypoglycaemia - convulsions, inability to swallow, loss of consciousness, coma (4-10% deaths due to hypoglycaemia)

Answer 7

Non-diabetic person: insulin continually released to provide background (basal) insulin to meet continuous metabolic demands, after meal/snack, a bolus of insulin released in proportion to the carbohydrate load eaten

Answer 8

• Measure HbA1c and BMI • Reiterate targets for HbA1c and glucose self monitoring - 4 x per day (including before meals and before bed), more if doing sport, pregnant, travelling - Fasting plasma glucose level of 5-7 mol/L on waking - Plasma glucose level of 4-7 mol/L before meals at other times of the day - For adults who choose to test after meals, plasma glucose level of 5-9 mmol/L at least 90 minutes after eating • Check BP, full lipid profile, thyroid profile, renal profile, ACR urine sample • Check attending screening appts for eye disease and foot problems • Check smoking status - discuss cessation if applicable • Assess mood (depression, anxiety, eating disorders) • Monitor for neuropathy (erectile dysfunction, neuropathic pain, delayed emptying of stomach) • Check injection sites - check it's being rotated, no lipohypertophy (lumps under skins) • Review hypo awareness (see DVLA info) and weight (s/e weight gain - insulin is a growth hormone so you get hungry) • Check been offered flu vaccination

Answer 9

Januvia - sitagliptin phosphate DPP4 inhibitor: aromatic compound(phenyl ring and pyrrolidine) with a trifluorophenyl group and a trifluoromethyl group pKa=8.78 Ionisation: largely ionized at body pH(7.40) Mechanisms of action Inhibit dipeptidylepeptidase-4(lead to the degradation of incretin hormones GLP-1 & GIP) to increase insulin secretion and lower glucagon secretion Bioavailability Good orally bioavailability---The absolute bioavailability of sitagliptin is approximately 87 %. CF3 group is lipophilic and will interact with a lipophilic group on DDP-4. Metabolism Very little metabolism--- sitagliptin is primarily eliminated unchanged(79%) in urine The presence of the three fluorine groups of sitagliptin will block metabolism in the liver of this tetrasubstituted phenyl ring A phenyl ring is typically susceptible to metabolism--- C-H oxidising to a phenol (C-OH). IMPROVEMENTS? Januvia Contains sitagliptin an orally active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely related enzymes DPP-8 or DPP-9 at therapeutic concentrations. Pka 8.78 strongest basic Ionisation Physiological charge 1 At physiological PH the amine group can exist in both protonated and unprotonated forms. Bioavailability 87% Metabolism Metabolism in the liver by CYP3A4 and CYP2C8, 79% excreted in urine as unchanged drug 1 (less fast pass metabolism) Has an oral bioavailability of 87% and a terminal Hal life of 10 to 12 hours 79% of dose excrete in the urine as the unchanged parent compound ———————————— JANUMET Janumet - sitagliptin phosphate & metformin hydrochloride DPP4 inhibitor + biguanide Metformin: 2 guanidine, amine pKa= 12.4 Ionisation: largely ionized at body pH + Metformin: Decrease gluconeogenesis Decrease intestinal absorption of glucose Increases insulin sensitivity by increasing peripheral glucose uptake and utilization Metformin: Approximately 50-60%. Food decreases the extent and slightly delays the absorption of metformin. Metformin is excreted unchanged in the urine. No metabolites have been identified in humans. IMPROVEMENTS?? A combination of sitagliptin and metformin hydrochloride. Metformin decreases hepatic glucose production and improves insulin sensitivity Metformin is an antihyperglycemic agent which improves glucose tolerance In patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilisation. Metformin may act via three mechanisms: 1. by reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis 2. in muscle, by modestly increasing insulin sensitivity, improving peripheral glucose uptake and utilisation 3. by delaying intestinal glucose absorption. Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase. Metformin increases the transport capacity of specific types of membrane glucose transporters (GLUT-1 and GLUT-4). 12,4 strongest basic Physiological charge at physiological PH metformin exists in ionised form. 50-60% excreted as unchanged drug in the urine (renal tubular excretion) and does not undergo hepatic metabolism (no metabolites have been identified in humans) or biliary excretion Tubular Secretion Bioavailability: 1 Metabolism: excreted unchanged in urine and doesn’t undergo hepatic metabolism or biliary excretion - active process so check for drug drug ingercatiosn Primary secondary and tertiary amine

Answer 10

Release glucagon (Fuel mobilising hormone)

Answer 11

Enzyme Glucose generated by digestion of starch or lactose is absorbed in the small intestine by co-transport with sodium The transporter that carries glucose and galaciose into the enterocyte ( intestinal wall cells ) is the sodium-dependent hexose transporter, SGLUT-1 If doesn’t work, stops glucose getting into body (Type 2)

Answer 12

Hormones GIP (gastric inhibitory peptide): in small intestine GLP-1 (glucagon like peptide) : in ileum & ascending colon Stimulate insulin production Side effects if these injected as drugs: causes overdrive of pancreas > pancreatitis (life threatening , inflammation of pancreas)

Answer 13

Binds to receptor (GIPR/ GLP-1R) Increases levels of calcium into beta cells This causes them to release insulin These get degraded quickly by DPP4 (dipeptidyl peptidase 4) > less insulin secreted To prevent degradation in T2 diabetes, DPP4 inhibitors used GLP-1 decreases hunger, inhibits gastric emptying, inhibits glucagon secretion and glucose production (good for diabetes to keep weight down)

Answer 14

Peptide hormone Synthesised as a precursor (preproinsulin) in the rough endoplasmic reticulum Preproinsulin undergoes proteolytic cleavage to proinsulin and then to insulin plus a fragment of uncertain function called C-peptide (less C-peptide = not enough insulin)

Answer 15

Other autoimmune conditions and psychological complications - Increased risk of thyroid disease (Grave's or Hashimoto's thyroiditis) so TSH levels checked in annual checks to make sure they aren’t high, autoimmune gastritis, pernicious anemia, coeliac disease, vitiligo, Addison's disease - Anxiety, depression, needle-phobia, edunoronsorders - Reduced life expectancy, 11-15 years Complications • Infections - More prone to infections (skin and urinary tract) Severe infections, amputations

Answer 16

Sub cutaneous insulin Can be insulin pumps (fast acting) > input carbs and pump calculates insulin (expensive to buy yourself & mainly prescribed for those who cannot achieve HbA1C targets & have hypos despite care)

Answer 17

insulin continually released to provide background (basal) insulin to meet continuous metabolic demands after meal/snack, a bolus of insulin released by pancrease in proportion to the carbohydrate load eaten Decreases again

Answer 18

Rapid acting (analogue) Before meal. Onset 5-15mins. Prevents hypos. Used with intermediate or long acting background insulin. injected at night time (Multiple injection therapy) Short acting Before meals. Onset 30-45mins but takes 2-4hrs to peak and actually work. Not great. Combined with intermediate/long acting background insulin (basal bolus) or in a free mix. Intermediate acting (longer duration of action compared to rapid and short acting, but absorption more erratic and less predictable than long acting insulin). Taken in morning & evening. Twice per day. Onset 2-4hrs peak action 4-6.hrs. Duration 8-14hrs. On own or combination with analogue / short. Cloudy insulin so mix well before use. Long acting analogues (Levemir& lantus) With short. Levemir once/twice daily.12-18hrs. Lantus once daily. 18-24hrs duration. Premixed (bit of long and small)

Answer 19

• Produces an insulin profile that is closest to natural insulin production by the body • Short acting soluble or rapid acting analogue insulin at meal • Intermediate or long acting insulin usually before bed • Offers greater flexibility for people with irregular lifestyle pattern

Answer 20

• Premixed short acting and intermediate insulin • Generally twice daily • Suits people with regular lifestyle pattern • Mixtures - not re-suspending alters mix

Answer 21

HbA1c - glycated haemoglobin level - Persistent high blood glucose levels leads to increased glycation of proteins including heamoglobin - HbA1c used to clinically monito long term glycemic control in diabetes - Gives picture of how much glucose has been in blood for last 2-3 months (lifespan of a red blood cell) - HbA1c target = 48 mol/I to minimize risk of long term vascular complications - At home people can monitor blood glucose levels with a handheld blood glucose meter (drop of blood needed) Insulin passport also used to see how much insulin used /last review

Answer 22

Less than 3.6mmol/L • Hunger, anxiety, irritability, sweating, tingling lips • Cognitive function deteriorates when blood glucose less than 3 mmol/I • Driving - carry fast acting card - check BG before journey and then every 2 hours - if BG low, stop care in safe place, switch engine off, move out of driver's seat and have something sugary, wait 45 mins until BG normal (carry snacks > lucozade energy, jelly babies, no sugar free drinks Advise people with diabetes that it is the responsibility of the driving licence holder or applicant to notify the Driver and Vehicle Licensing Agency (DVLA) of their medical condition

Answer 23

Not high CVD risk: Metformin / metformin MR if GI disturbance eg tummy ache/ bloating. CVD risk: optimise metformin to about 1.5mg /day (500mg 3x/day) + SGLT2 inhibitor (end with flozin eg empaglifozin > cardiovascular benefit & protection. Reduces risk of HA/S. Gliclizide = rescue drug. Rapidly reduces blood glucose. 7-10 days Initially consider cv status. Individualised approach (tailored HbA1C targets) to achieve & maintain Offer DESMOND (diabetes education programme for type 2 patients & family/carers) Measure HbA1C every 3/6 months until stable then every 6 months Can try diet & activity change first 3 months if would like If diet & or metformin > HbA1C target 48mmol / mol (can change a bit more relaxed 50/51) If on sulfonylurea eg Gliclizide as well > 53 If on dual therapy eg with empagliflozin > 53 Reinforce diet & lifestyle advice, adherence

Answer 24

Metformin is a BIGUANIDE and is very basic.. pKa 11.5 - exists as a cation and is positively charged (1 mark) After ingestion, cationic metformin is transported into the liver (hepatocytes) by the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes. As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane (1 mark) Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios (1 mark) These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism (1 mark)

Answer 25

Reduces peripheral insulin resistance, leading to a reduction of blood glucose concentration Benefits • Risk of hypoglycaemia - rare Cautions • Do NOT start or continue pioglitazone in people who: • have heart failure (NYHA class I-IV) • history of heart failure • diabetic ketoacidosis are at a higher risk of fracture • macular oedema • hepatic impairment • current bladder cancer or a history of bladder cancer • patients with uninvestigated macroscopic or microscopic haematuria

Answer 26

• Increase insulin secretion, suppress glucagon secretion, slow gastric emptying and reducing appetite and food intake If triple therapy with metformin and 2 other oral drugs is not effective, not tolerated or contraindicated, consider triple therapy by switching one drug for a GLP-1 mimetic for adults with type 2 diabetes who: • have a body mass index (BMI) of 35 kg/m? or higher (adjust accordingly for people from Black, Asian and other minority ethnic groups) and specific psychological or other medical problems associated with obesity or • have a BMI lower than 35 kg/m2 (lower of ethnics) and: - for whom insulin therapy would have significant occupational implications or weight loss would benefit other significant obesity related comorbidities Benefits • Weight loss - which can be modest in most patients, but significant in some • Low hypoglycaemia • CV benefits Cautions • Type 1 diabetes • Pregnancy • Breastfeeding • Acute pancreatitis (rare but serious) - weekly preparations vs daily • Weekly preps useful if compliance issues

Answer 27

NICE recommend that patients with diabetes should receive the following nine key tests/processes at least once a year: • HbA1c (tailored to individual needs) • Blood pressure aim: <140/90mmHg (but check ACR as targets may be different - NICE Guidelines Type 2 diabetes) • Cholesterol (full lipid profile) - QRISK if appropriate • Weight aim: BMI of 18.5 - 24.9 • Smoking status - discuss cessation if applicable • Urinary albumin (aim: <2.5mg/mol for men, <3.5mg/mmol for women) Serum Creatinine (>150 micromol/L - check if doses of medication need amending) • Eye examination • Foot examination (risk scored as low, moderate and high) • Check been offered flu vaccination and pneumococcal vaccination

Answer 28

• Age - less stringent HbA1c targets with decreasing life expectancy • Body weight - consider which drugs affect body weight - weight neutral - metformin and DPP4i (gliptins), weight gain - insulins, pioglitazone, sulphonylureas, weight loss - SGLT I and GLP1 • Complications - coincident complications will impact drug selection e.g., patient with eGFR< 30ml/min/1.73m2 should avoid metformin (lactic acidosis - metformin increases plasma lactate conc by inhibiting mitochondrial respiration, mainly in the liver. Increased concentration of plasma metformin (such that which occurs in patients with worsening renal function) = metformin-associated lactic acidosis • Duration - disease duration is a consideration when setting HbA1c levels. - shorter the disease duration the greater the cardiovascular protection offered by strict glycemic control once disease duration is 10-12 years the beneficial effects of strict glycemic control may be lost or reversed. Reassess the person's needs and circumstances at each review and consider discontinuing any medicines that are not effective

Answer 29

Substrate Binding: DPP4 binds to peptides with a proline or alanine residue at the second position from the N-terminal. Nucleophilic Attack: The hydroxyl group of Ser630 in the active site attacks the carbonyl carbon of the amide bond, forming a tetrahedral intermediate. Histidine's Role: His740 acts as a base, accepting a proton from Ser630, increasing the nucleophilicity of serine. Aspartate Stabilization: Asp708 stabilizes the positive charge on histidine during the reaction. Intermediate Collapse: The tetrahedral intermediate collapses, breaking the amide bond and forming an acyl-enzyme complex. Water Activation: A water molecule, activated by histidine, attacks the acyl-enzyme intermediate, leading to hydrolysis. Product Release: The cleaved dipeptide and remaining peptide fragment are released, regenerating the enzyme's active site for the next reaction. This mechanism explains how DPP4 cleaves peptides by hydrolyzing the amide bond, using its catalytic triad (Ser630, His740, and Asp708) and water to complete the reaction.