YR1 Lecture 1H - Aetiology T2D Met Syndrome - 1H 2022.pdf

Aetiology of Type 2 Diabetes and the Metabolic Syndrome Lili Yuen Endocrinologist 9 May 2022 [email protected] 1 Learning objectives Apply knowledge of the metabolic actions of insulin to discuss the acute metabolic consequences of insulin deficiency Discuss available management options...

Aetiology of Type 2 Diabetes and the Metabolic Syndrome Lili Yuen Endocrinologist 9 May 2022 [email protected] 1 Learning objectives Apply knowledge of the metabolic actions of insulin to discuss the acute metabolic consequences of insulin deficiency Discuss available management options for patients with obesity, Type 2 diabetes and hyperlipidaemia Discuss the aetiology and pathophysiological basis of Type 2 diabetes mellitus Identify factors that can impact on the outcome of suggested management strategies and goals 2 Overview Insulin Resistance Obesity Metabolic Syndrome Type 2 Diabetes Treatment 3 The Pancreas Named from Greek words pan (all) and kreas (flesh) 12-15cm J-shaped soft, lobulated retroperitoneal organ Embryologically develops as 2 buds of endoderm from the primitive duodenum at the junction of the foregut and midgut Because the CBD arises also from the ventral bud, it forms a common channel with the main pancreatic duct (of Wirsung) to form a common channel (ampulla) Functions of the Pancreas Composed of both exocrine and endocrine components Exocrine pancreas: Acinar cells secrete digestive enzymes (CCK, trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, lipase nucleases and amylase) that break down C-OH, proteins, fats and acids in duodenum Regulated by secretin and cholecystokinin hormones Enzymes secreted into ducts that join the main pancreatic duct Endocrine pancreas: Consists of islets of Langerhans Secretes hormones: 𝛼 cells (20%) – glucagon ß cells (65-80%) – insulin, c-peptide and amylin 𝛿 cells ( 40 kg/m2 Source: ABS National Health Survey 2014-15: http://www.smh.com.au/national/health/australians-are-fat-and-unfit-but-at-least-we-are-drinking-and-smoking-less-20151207-glhycn.html 21 Obesity The distribution of adipose tissue in different anatomic depots has substantial implications for morbidity Intra abdominal and abdominal subcutaneous fat are associated with greater metabolic implications than subcutaneous fat present in buttocks and lower extremities Clinically use of waist-to-hip ratio to determine distribution: Waist is mid-point of lowest rib and top of iliac crest Hip is measured across the widest portion of the buttocks Harris, MF. “The metabolic syndrome”. Aust Family Phys. Volume 42, No.8, August 2013 Pages 524-527. http://www.racgp.org.au/afp/2013/august/the-metabolic-syndrome/ Sequelae of Obesity More likely to develop metabolic syndrome, cardiovascular disease and type 2 diabetes Obesity has been implicated with increased mortality, with a 50 – 100% increased risk of death from all causes compared to normal – weight individuals, mostly due to cardiovascular causes Insulin resistance is more strongly linked to intra abdominal fat accumulation: Insulin excess may induce receptor downregulation Free fatty acids are increased and capable of impairing insulin action Intracellular lipid accumulation Several circulating peptides produced by adipocytes, including cytokines TNFα and IL-6, RBP4, and adipokines (adiponectin and resistin) which have altered expression Possibility of obesity-linked inflammation to cause insulin action resistance in cells Other Consequences of Obesity Reproductive disorders: Males: ↓testosterone and sex-hormone binding globulin (SHBG), ↑ oestrogen  gynaecomastia Females: menstrual abnormalities, ↑ androgens, ↓SHBG, ↑ conversion of androgen to oestrogen, PCOS Pulmonary disease: ↓ chest wall compliance, ↑work of breathing, ↑ minute ventilation due to increased metabolic rate, ↓ functional reserve capacity and expiratory reserve volume Obstructive sleep apnoea and obesity hypoventilation syndrome Hepatobiliary disease: Nonalcoholic fatty liver disease (NAFLD) → inflammatory non alcoholic steatohepatitis (NASH) → cirrhosis and hepatocellular carcinoma (HCC) Gallstones: enhanced biliary secretion of cholesterol, supersaturation of bile Cancer: Males: oesophagus, colon, rectum, pancreas, liver, prostate Females: gallbladder, bile ducts, breasts, endometrium, cervix and ovaries Bone, joint and cutaneous disease: OA: trauma and added weight bearing, activation of inflammatory pathways Gout Venous stasis Acanthosis nigricans: reflects degree of insulin resistance, can lead to skinfold infections Treatment Options for Obesity Patients with obesity-related complications and who would benefit from weight loss intervention should be managed proactively 3 options: Lifestyle: modest weight loss (typically 3-5kg) Pharmacotherapy Surgery: gastric banding weight loss ~ 20-25%. Other procedures ~ 30-35% T2D remission in 68.2% at 5 years with ⅓ redeveloping diabetes at 5 years. Controversy as to whether all who have high BMI alone need treatment: ?Concept of “Metabolically Healthy Obese” Lifestyle Therapy - Diet Goal is to reduce overall calorie consumption E.g. 500-1000kcal/day reduction for ~250-500g weight loss/week Through portion sizes, dietary substitutions or alternatives Examples: Mediterranean, lowcarbohydrate, meal replacements, lowenergy density Very Low Energy Diet (VLED): causes rapid weight loss. Needs close monitoring and management if patient has diabetes Works best when dietary counselling is patient centred and goals are practical, realistic and achievable Lifestyle Therapy - Exercise Only moderately effective for weight loss Combination with dietary modification is most effective behavioural approach for obesity treatment Important for maintenance of weight loss Current recommendations are adults should engage in 150 minutes of moderate-intensity or 75 minutes of vigorousintensity aerobic physical activity per week Use of step counters are highly correlated with activity level A high level of physical activity is needed (>300 minutes of moderate-intensity activity per week) to lose and sustain weight loss Pharmacotherapy for Weight Loss Phentermine: (in US combined with Topiramate) Increases catecholamine release Increases satiety and reduces hunger Short term use, not to be used with MAOI, pre-existing CVD Topiramate: Anticonvulsant and used for migraine prophylaxis Weight loss is an unintended side effect, thought to be mediated through modulation of 𝛾-aminobutyric acid receptors, inhibition of carbonic anhydrase and antagonism of glutamate Orlistat (Xenical™): Synthetic lipase inhibitor, blocks digestion and absorption of ~30% dietary fat in stomach and small intestine Liraglutide (Saxenda®) & Semaglutide (Ozempic® - off label): GLP-1 receptor agonist used in T2D in smaller doses Independent weight loss effect via hypothalamic neural activation causing appetite suppression Source: Harrison’s Endocrinology 4th ED Overview Insulin Resistance Obesity Metabolic Syndrome Type 2 Diabetes Treatment 31 The Metabolic Syndrome This plus Any TWO of the these Harris, MF. “The metabolic syndrome”. Aust Family Phys. Volume 42, No.8, August 2013 Pages 524-527. http://www.racgp.org.au/afp/2013/august/the-metabolic-syndrome/ Lipids Lipids are fats that are either absorbed from food or synthesized in the liver, which function to store energy in adipocytes and muscle cells Cholesterol is an ubiquitous constituent of cell membranes, signalling molecules and bile acids As lipids are hydrophobic and insoluble in blood, they require transport within structures called lipoproteins which possess surface proteins – apoproteins, that are cofactors and ligands for lipid-processing enzymes Lipoproteins are classified by size and density (ratio of lipid to protein) High density lipoproteins (HDLs) Low-density lipoproteins (LDLs) Intermediate-density lipoproteins (IDLs) Very-low density lipoproteins (VLDLs) Over 95% of dietary lipids are triglycerides Triglycerides and high levels of LDLs and low levels of HDL have been implicated in cardiovascular disease 33 Hyperlipidaemia The presence of elevated or abnormal levels of lipids ± lipoproteins This is classified into Primary or Secondary Hyperlipidaemia Primary Hyperlipidaemia Frederickson classification – based on which plasma concentrations were increased From: Christopher B. and Abdelaal Y. Severe dyslipidaemia in ayymptomatic patient. Hospital Doctor of Ireland. September 2015. 21; 34 7 Secondary Hyperlipidaemias Many causes, can be present concurrently with primary hyperlipidaemia Obesity Diabetes mellitus Metabolic syndrome Hypothyroidism Nephrotic syndrome Cholestasis – e.g. primary biliary cirrhosis Systemic lupus erythematosus Acute intermittent porphyria Anorexia nervosa/bulimia Alcohol excess Exercise Drugs e.g. ciclosporin, oestrogen, fibrates, nicotinic acid, statins, phenytoin, rifampicin, ß-blockers, thiazide diuretics, protease inhibitors, neuroleptics, glucocorticoids 35 Management of Dyslipidaemia Recommend lifestyle modification for all at risk: Dietary advice: low saturated fat, trans fat, cholesterol Physical activity: regular moderate to physical intense exercise (at least 30 minutes most days) Smoking cessation Salt restriction ≤ 4g/day (65mmol/day sodium) Limit alcohol intake ≤2 standard drinks per day for males, ≤1 standard drink for females Lipid-lowering therapy for primary prevention should (while balancing risks and benefits) aim towards: total cholesterol