Adult Diabetes Mellitus and Hyperglycemic Disorders (Final) PDF

Module 05: Endocrine [Clinical Medicine] Adult Diabetes Mellitus and Hyperglycemic Disorders Nemencio Nicodemus Jr., M.D. | September 26, 2023 TABLE OF CONTENTS FIGURE 1 LEARNING OBJECTIVES I....

Module 05: Endocrine [Clinical Medicine] Adult Diabetes Mellitus and Hyperglycemic Disorders Nemencio Nicodemus Jr., M.D. | September 26, 2023 TABLE OF CONTENTS FIGURE 1 LEARNING OBJECTIVES I. DIABETES IN THE PHILIPPINES The Department of Science of Technology and Health and II. REVIEW Food and Nutrition Research Institute regularly conducts A. NORMAL PHYSIOLOGY survey in the Philippines nationwide (published 2018, updated B. GLUCOSE 2019) C. MECHANISMS OF INSULIN ACTION The number of Filipino adults, aged 20 years and above with D. ACTIONS OF INSULIN elevated FBS of 126 mg/dL and above is at 8.1% E. BLOOD GLUCOSE HOMEOSTASIS ○ A lot higher than the 3.9% when started doing the survey in III. DIABETES MELLITUS 1998 A. DEFINITION ○ Has more than doubled in over 20 years B. ETIOLOGIC CLASSIFICATION OF DIABETES Blue line: FBS between 110-125 mg/dL MELLITUS ○ Will play an important role when we talk about the C. TYPE 1 DIABETES spectrum of disorders in our patients D. TYPE 2 DIABETES E. RISK FACTORS FOR DIABETES F. CLASSIC SYMPTOMS OF DIABETES MELLITUS G. DIAGNOSIS OF DIABETES & PRE-DIABETES H. RELATIONSHIP OF DIABETES-SPECIFIC COMPLICATION AND GLUCOSE TOLERANCE I. PATHOGENESIS OF T2DM J. CENTRAL REGULATION OF APPETITE K. THE EGREGIOUS ELEVEN L. COMPLICATIONS OF DIABETES M. MANAGEMENT AND TREATMENT N. ESSENTIAL ELEMENTS IN COMPREHENSIVE CARE OF T2DM O. HOLISTIC PERSON-CENTERED APPROACH TO Figure 2. Top 10 Causes of Death in the Philippines T2DM MANAGEMENT IV. QUICK REVIEW FIGURE 2 V. REFERENCES A. REQUIRED Over the last 10 years, before COVID-19 VI. FREEDOM SPACE ○ In the Philippines, diabetes is the 6th leading cause of death in adults LEARNING OBJECTIVES Top 1 is ischemic heart disease Top 2 is stroke 1. Review the processes involved in glucose homeostasis Did this data change after COVID-19 (2020-22)? 2. Discuss the presentation, pathophysiology, diagnosis and ○ Even if COVID-19 was an important comorbid condition latest recommendations in the management of hyperglycemia was not able to replace IHD and stroke as the leading in people with diabetes mellitus cause of death in our country 3. Discuss the presentation, approach to the differential Diabetes remains at number 6 diagnoses and management of hypoglycemia The non-communicable diseases are not at all affected by COVID I. DIABETES IN THE PHILIPPINES ○ In fact, there are more people who got obese over the course of the pandemic due to stay-at-home protocols, food take outs, etc. II. REVIEW A. NORMAL PHYSIOLOGY In normal physiology, whenever we eat a mixed meal, it gets digested and eventually gets absorbed ○ Nutrients are absorbed in the different parts of the gut Monosaccharides (simple form of carbohydrates) are absorbed in the jejunum of the small intestine Once in the blood, glucose travels to the portal vein and Figure 1. DOST Survey eventually enters the circulation to stimulates very important hormones that will make sure that your glucose levels in the blood are within normal range YL7: TG 07: Almuete, Benedicto, Catindig, Chen, Narciso, Placides, Porca, Villaseñor 1 of 05.09a CG 12: Cajayon, Carlos, Cua, De Leon, Enriquez, Jang, Reyes, Santiago, Sim, Yanzon, Ybiernas 16  — This main organ is the pancreas It is the Islet of Langerhans which is the major histological structure where we can find the cells that regulate glucose metabolism Figure 6. Islet of Langerhans FIGURE 6 Beta cells are the predominant cells in the Islet of Langerhans ○ Comprise > 50% of the cells Figure 3. GI Tract ○ Secretes insulin Alpha cells ○ Tend to occupy the peripheral part of your Islet of Langerhans ○ Secretes glucagon Counter regulatory to insulin Delta cells ○ Secretes somatostatin F cells ○ Secretes pancreatic polypeptide B. GLUCOSE Figure 4. Absorption in the Jejunum FIGURE 4 Monosaccharides (simple forms of carbohydrates) get absorbed in the jejunum Figure 7. Glucose as key regulator of insulin secretion FIGURE 7 What makes your beta cells secrete insulin? Glucose Glucose will enter beta cells: ○ By means of glycolysis Figure 5. Digestion ○ Glucose is converted to glucose 6-phosphate→ Citric Acid cycle (aka Krebs) via your pyruvate → goes to the electron FIGURE 5 transport chain → ATP production As ATP increases in beta cells Once in the blood, glucose travels and goes to the portal vein ○ ATP/ ADP ratio rises → circulation to stimulate important hormones in the pancreas Acts as a stimulus to close an ATP-sensitive K+ ○ Pancreas makes sure that glucose levels are within normal channel closes which limits the entry of K+ into the beta range cells → Depolarization Islet of Langerhans: major physiological structure where you The depolarization creates opening of voltage-sensitive can find important cells that regulate glucose metabolism calcium channels ○ Calcium will enter the beta cells Calcium act as a very important intermediate/mediator for the movement of granules which contain mature YL7: 2 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  insulin from cytoplasm to cell membrane where insulin is C. MECHANISM OF INSULIN ACTION released into the circulation 1st phase counters glucagon - for it to be countered, it needs very high insulin 2nd phase is to maintain reduction of blood glucose Figure 8. Insulin Released in Two Episodes Figure 10. Insulin Action FIGURE 8 FIGURE 10 In the circulation, insulin is secreted in two episodes After insulin is released from the beta cells → directly poured ○ 1st episode into the blood/capillaries Initial rapid release of insulin within first 5 minutes ○ Recall: Islet of Langerhans are endocrine organs (no of eating 1st phase insuln ducts) hence the insulin can go directly to the blood — Due to the presence of preformed granules (refer to Once insulin encounters an organ that has insulin receptors, Figure 6) since insulin is constantly being produced then the insulin starts to act by means of transcription and translation One such important organ in our body that has a lot of insulin — There are already ‘ready’ insulin, hence, it can be receptors are our muscles out/released in the first 5 mins but if this batch runs ○ One of the major organs that respond to insulin action out already persist for the next 10-15 minutes, then goes down but never 0 — A next one should be ready, hence, the 2nd episode ○ 2nd episode 2nd insulin response Happens after 20-30 minutes of eating The two episodes are very important in controlling the sugar levels in your blood ○ That is why we don’t get excessive hyperglycemia Figure 11. Molecular Mechanism of Insulin Action in the Organs a-subunit b- subunit FIGURE 11 Insulin binds to its receptor, which has α and β subunits Tyrosine kinase autophosphorylates the insulin receptor ○ Recall: Binding causes autophosphorylation of the receptor by means of the kinases By a cascade of phosphorylation events, it now triggers the translocation of the vesicles that contain glucose transporters from the cytoplasm to the cell membrane Figure 9. Insulin Pattern after a Meal Glucose transporters will now allow glucose to enter the cell ○ Action of insulin in the muscle is to allow glucose to enter the muscle for energy (glucose → ATP) FIGURE 9 As we breakfast, lunch, and dinner our sugar increases (refer to the lower graph in the figure) Insulin secretion follows your meal intake ○ The 1st phase and the 2nd phase insulin responses would always be present ○ The magnitude will depend on how much you ate The more carbs you eat, the more insulin there will be \\ YL7: 3 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  D. ACTIONS OF INSULIN high glucose may not manifest at all diabetes may not manifest with any symptoms at all --> until you have complications insulin reduces all catabolic processes no insulin --> lipolysis (fat breakdown) --> DM patients can lose weight Figure 14. Diabetes Mellitus Figure 12. Actions of Insulin in Terms of Metabolic Processes Diabetes mellitus: group of metabolic diseases FIGURE 12 ○ Common to these disorders is they either have a defect in: Insulin secretion Insulin goes to the tissues where it binds to the receptors Insulin action ○ In most tissues: — Particularly with the receptors and phosphorylation Triggers uptake of glucose, such as in the muscles Both insulin secretion and action Stimulates amino acid uptake ○ The effect is hyperglycemia Stimulates protein synthesis Glucose cannot enter the cell because glucose Prevents protein breakdown transporters are not allowed to go in the cell membrane ○ In adipose tissues: ○ If the body persists to have elevated blood glucose, it will Stimulates fatty acid and triglyceride synthesis now cause long-term damage Prevents lipolysis ○ In the liver and muscle: B. ETIOLOGIC CLASSIFICATION OF DIABETES MELLITUS Increases glycogen synthesis Inhibits the breakdown of glycogen (glycogenolysis) ○ In the liver: Promotes fatty acid and triglyceride synthesis Prevents gluconeogenesis Insulin is mainly an anabolic hormone as it promotes storage and synthesis E. BLOOD GLUCOSE HOMEOSTASIS Figure 15. Etiologic Classification of Diabetes Mellitus 4 main etiologic classifications ○ Hence, diabetes mellitus is a group of metabolic diseases and not just one entity Type 1 and Type 2 Diabetes Mellitus comprise the majority of diabetes all over the world Gestational diabetes mellitus affects a special population of patients C. TYPE 1 DIABETES PATHOPHYSIOLOGY Figure 13. Blood Glucose Homeostasis FIGURE 13 If the blood glucose level is high ○ Beta cells secrete insulin ○ Insulin insert their action in most of the body cells, including the liver ○ Glucose will be taken up ○ Glucose level in your blood normalizes Diseases occur when the normal physiological actions and processes in our body go haywire Figure 16. Pathophysiology of Type 1 Diabetes Immune mediated (autoimmune) III. DIABETES MELLITUS ○ Differentiates Type 1 diabetes from other types in terms of A. DEFINITION etiology YL7: 4 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  ○ Mainly mediated by the immunological processes that Zinc transporter 8 Present in 80% of patients happen in the body autoantibodies (ZnT8Ab) with type 1 diabetes, with Due to β-cell destruction 99% specificity ○ Usually leading to absolute insulin deficiency Provides an independent Idiopathic measure of autoreactivity, as 25-30% of type 1 diabetes patients negative for IAA, GAD, and IA-2 are ZnT8Ab positive hla gene TABLE 1 - predisposition to T1DM Anti-GAD - also virus ○ Major autoantibody ○ Recall: Glutamic acid decarboxylase is present in mitochondrial enzymes as part of electron transport chain NICE! Tests for Anti-GAD, IAA and ICA are available in the Philippines Figure 17. How Type 1 Diabetes Might Arise ○ Therefore, we can definitely diagnose Type 1 diabetes in the country FIGURE 17 Autoantibody tests are expensive People with Type 1 diabetes are born with normal blood sugar ○ 1 test is around PhP 8000, and you need to have at least 2 ○ At least a majority of them do not manifest with tests hyperglycemia yet If you will tell your patient that they will be on insulin for life, Some may have hyperglycemia already then you must be able to prove that they really need insulin ○ Hence why not all cases are detected ○ You have to diagnose Type 1 diabetes accurately There is usually an environmental trigger (e.g. viral or The only drug that they will respond to is insulin bacterial infection) ○ Triggers the body to produce antibodies that can attack CLINICAL FEATURES β-cells because these antigens may be similar to the proteins present in the β-cells Table 2. Clinical Features at Presentation that Help to Distinguish Type 1 and Once you have these environmental triggers, the body starts Type 2 Diabetes starts at young age to create CD8 cells, antigen presenting cells, and eventually Type 1 Type 2 autoantibodies Weight loss Yes Unusual Autoantibodies destroy β-cells (though not always; No, unless patient Ketonuria e.g., in slow-onset has been fasting ○ Initially, there is a rapid decline in β-cell population Type 1) recently ○ Honeymoon Phase: β-cell population stabilizes Time course The decline tends to plateau Weeks or days Months to years for symptoms Blood sugar remains stable Often marked ○ Progressive decline until the development of progressive Sudden weight insulin deficiency Severity of Variable, but loss symptoms usually not severe Polyuria Polydipsia AUTOANTIBODY TESTS Possible family history of Table 1. Diabetes-specific Autoantibody Tests Family history autoimmune disease Autoantibody Specificity present in 30% Family history and/or insulin with onset in adult Anti-glutamic acid Present in 84% of patients with dependence at a life decarboxylase type 1 diabetes young age autoantibodies (anti-GAD) Not necessary Insulin autoantibodies (IAA) Presence of IAAS is dependent Peak age in Typically after the on age and sex: pre-school and age of 40, but can 81% of children under 10 Age teenage years, but present in younger with type 1 diabetes can be present an patients 61% in older patients any age In patients under 15, the presence of IAAS is TABLE 2 similar in both sexes In patients over 15, the Weight loss male:female ratio is 2:1 ○ Patients with Type 1 diabetes usually have weight loss, but Insulinoma-associated-2 Present in 58% of patients with not always autoantibodies (IA-2) type 1 diabetes Islet cell cytoplasmic Present in 70-80% of new Ketonuria autoantibodies (ICA) onset patients with type 1 ○ The presence of ketone bodies in the urine is almost diabetes always present in patients with Type 1 diabetes YL7: 5 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  ○ Recall: Ketones bodies come from excessive A family member who have obesity but not diabetes triacylglycerides may already have pre-diabetes E.g. β-hydroxybutyric acid, acetoacetate, acetone Genetic and environmental nature (eg. family eating Time course together) is an important trigger ○ Very quick for patients with Type 1 diabetes to develop symptoms WHO SHOULD UNDERGO LABORATORY TESTING FOR ○ Children develop symptoms all of a sudden within a period TYPE 2 DIABETES? (PHILIPPINE CLINICAL PRACTICE of weeks GUIDELINES) Namamayat, ihii nang ihi, nanghihina All adults age 40 and above High blood sugar on testing ○ Based on the DOST FNRI data, the number of people with diabetes in our country starts to rise rapidly at age 40 D. TYPE 2 DIABETES ○ May go down to 35 years old in the updated guidelines Earlier for individuals with risk factors for Type 2 diabetes ETIOLOGY mellitus Etiology of β-cell destruction in Type 2 diabetes is insulin E. RISK FACTORS FOR DIABETES resistance ○ People who develop Type 2 diabetes start with insulin HISTORY AND PHYSICAL EXAMINATION resistance ○ Recall: the etiology of Type 1 diabetes is autoimmune First degree relative with Type 2 diabetes Insulin resistance is triggered by obesity ○ Kayo po ba ay may tatay, nanay, o kapatid na may Type 2 diabetes? Physical inactivity NICE! ○ Kayo po ba ay aktibong tao? Or mostly physically active? The connection between COVID and the prevalence of History of gestational diabetes mellitus (GDM) or a delivery diabetes around the world is obesity of a baby weighing 8 lbs. or above ○ A lot of people developed insulin resistance during the ○ Kayo po ba ay may history ng GDM, or delivered a baby pandemic that weighed at least 8 lbs.? There was an increased number of people both in the ○ Note: Harrison’s says 9 lbs., which differs from the Philippines and throughout the world who developed obesity Philippine Clinical Practice Guidelines because of the pandemic The presence of acanthosis nigricans ○ Hyperpigmented, thickened patches that can be seen in the creases of the skin in the: excess fat --> insulin resistance - in obesity Axillary area Nape post prandial - first abnormal Groin eventually, fasting BS becomes abnormal too ○ Sign of insulin resistance ○ Can lighten up when you lose weight Figure 19. Acanthosis Nigricans COMORBID CONDITIONS Figure 18. Natural Progression of Type 2 Diabetes Check for the following when doing PE: FIGURE 18 ○ Obesity Considered as a comorbid disease/condition already Initially, the β-cells will try to counter the insulin resistance by ○ Hypertension (BP > 140/90 mmHg) creating more insulin ○ Diagnosis or history of any vascular diseases including: ○ The insulin levels will eventually do gown because the Stroke β-cells can only do so much Peripheral arterial disease ○ After a while, there will be β-cell exhaustion and β-cell Coronary arterial disease dysfunction ○ Polycystic ovarian syndrome (PCOS) Blood sugar starts to rise One of the most common endocrine disorders in women ○ Starting with the post-prandial blood sugar, then eventually Diagnosed both clinically and by ultrasound the fasting blood sugar will go up — Clinically: irregular menses, hyperandrogenism Pre-diabetes (orange shaded area) especially hirsutism, male pattern alopecia (e.g. in the ○ The blood sugar level is still within normal, but starting to back of the head and receding hairline) rise until the level where you diagnose diabetes — Ultrasound: cysts in the ovaries ○ A person who will eventually develop diabetes might have Women with PCOS have elevated serum testosterone pre-diabetes 10-15 years before ○ Schizophrenia (drugs given) ○ Screened by asking family history Schizophrenia in itself may not be a risk factor YL7: 6 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  But the psychotropic drugs given increase insulin following are major risk factors to developing a heart resistance and blood sugar attack/first myocardial infarction: ○ Pulmonary TB Elevated waist circumference Risk factor for diabetes in our country Elevated waist-hip ratio NICE! LABORATORY FACTORS Doc cautions himself whenever talking about people with obesity Check for: They are not “obese people,” but rather, they are “people with ○ Fasting blood glucose obesity.” Elevated = impaired fasting glucose (IFG) Similar to people with diabetes, people with hypertension ○ Post-prandial blood glucose of OGTT Obesity does not define a person Elevated = impaired glucose tolerance (IGT) ○ You are not an obese person, you are a person with ○ Both elevated FBG and post-prandial glucose are obesity pre-diabetic states History of IGT or IFG (pre-diabetes) HDL cholesterol < 35 mg/dL (0.9 mmol/L) and/or triglycerides ACTIVE RECALL BOX > 250 mg/dL (2.82 mmol/L) 1. T/F. Polycystic ovarian syndrome is a risk factor for ○ Risk factors for diabetes developing Type 2 diabetes 2. T/F. Acanthosis nigricans is a sign of insulin deficiency TAKE NOTE! If a patient’s lab workups come back with these results, you Answers: 1T, 2F have an idea that he/she is at risk of developing diabetes in the future PHYSICAL EXAMINATION Pre-obesity (formerly overweight) or obesity F. CLASSIC SYMPTOMS OF DIABETES MELLITUS Aside from obesity, patients can have acanthosis nigricans People often associate diabetes with the classic symptoms: How do you know if a patient has obesity? ○ Polyuria polyuria - most frequent ○ Well-established methods around the world: ○ Polydipsia fatigue - 2nd most frequent polydipsia - most predictive for BMI ○ Unexplained weight loss - unintentional DM weight loss - also predictive for Waist circumference Or weight loss despite increased appetite T2DM Waist-hip ratio Table 3. Symptoms Significantly Associated with Type 2 Diabetes Symptom Frequency Odds Ratio NICE! Frequent urination 33.8% 1.28 The CPGs for obesity in the Philippines will soon be released Increased fatigue 27.3% 1.19 Excessive thirst 20.0% 2.48 BMI Blurry vision 18.2% 1.58 Extreme hunger 9.5% 1.55 Using Asia-Pacific cut-offs Unusual weight loss 4.4% 1.68 Pre-obesity: 23-24.9 kg/m2 Erectile/sexual 18.3% 1.46 Obesity: ≥ 25 kg/m2 dysfunction Waist Circumference TABLE 3 If patient meets the following cut-offs, they are considered to have central obesity: The most frequent symptom of diabetes is polyuria ○ Females: ≥ 80 cm OR > 31.5 inches But the strongest predictor of diabetes is polydipsia ○ Males: ≥ 90 cm OR > 34.5 inches But if all 3 are present, the likelihood of you having Where do you measure your waist? diabetes is higher ○ Standard way: midpoint between lowest rib/costal 44% of type 2 diabetes respondents reported no cartilage and anterior superior iliac spine (ASIS) symptom in the previous year ○ Patient does not need symptoms to be diagnosed with Waist-Hip Ratio diabetes Hip circumference is taken from the widest diameter of the ○ As much as 4 in 10 will not present with symptoms at all buttocks ○ Have an index of suspicion: Get the ratio between the waist and hip circumference Does the patient have obesity? If patient meets the following cut-offs, they are considered to Does the patient have a first-degree relative with have central obesity: diabetes? ○ Females: ≥ 0.85 risk for heart attack is related to wasit Ask for all other risk factors to improve your suspicion of circumference and waist to hip ratio ○ Males: ≥ 1.0 possible diabetes TAKE NOTE! 4/10 pts have no symptoms - DM not diagnosed by Doc would prefer if we use the waist circumference and symptoms alone but by waist-hip ratio glucose levels ○ An international study (INTERHEART Trial), which included the Philippines as its major site was able to show that the YL7: 7 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  G. DIAGNOSIS OF DIABETES & PRE-DIABETES FIGURE 21 Why is the cut-off 126 mg/dL? Why is it 200 mg/dL? ○ They came from an epidemiological study looking at the chances of developing retinopathy due to high blood sugar By the time your FPG, 2-h PG, and HbA1c reach the levels of the cut-offs, there is a rapid rise in the chance that you will develop retinopathy → they used these cut-offs to diagnose diabetes due to the development of complications — Shows that the cut-off values have a basis — Values are not random Figure 20. Diagnostic Criteria for Diabetes & Pre-Diabetes I. PATHOGENESIS OF T2DM Very objective way to diagnose: get the level of blood Diabetes is a complicated disease glucose ○ Not just a matter of insulin resistance Our understanding of diabetes continues to evolve FIGURE 20 One of the most important discoveries of the past century was Red areas: cut-offs for saying that the patient is diagnosed the pathophysiology of diabetes with diabetes mellitus ○ FBG: at least 126 mg/dL ○ 75 g OGTT: at least 200 mg/dL after 2 hours of intake of 75 g glucose ○ HbA1c: at least 6.5% Green areas: normal ○ FBG < 100 mg/dL ○ 75 g OGTT: < 140 mg/dL after 2 hours of intake of 75 g glucose ○ HbA1c: < 5.7% Yellow areas: pre-diabetes need 2 of these, ○ FBG: referring to IFG dont need 3 tests ○ 75 g OGTT: referring to IGT Figure 22. The Ominous Octet of Diabetes Mellitus TAKE NOTE! FIGURE 22 Doc said to remember these values, since they are basic numbers whenever talking about the glucose continuum In 2008, Professor Ralph DeFronzo delivered a very important ○ Sugar is a continuum, it does not stop speech during the annual convention of the American ○ Sugar can swing from one number to another Diabetes Association How many times should you have abnormal blood glucose ○ He said that diabetes is due to 8 major abnormalities in levels to diagnose diabetes mellitus? the body, termed as the “ominous octet” ○ At least twice in a period of 12 weeks → repeat the test Impaired insulin secretion 1. Insulin - within 12 weeks before you can diagnose with diabetes Decreased glucagon secretion 2. Glucagon + 3. Liver glucose + Increased hepatic glucose production 4. Muscle glucose - 5. Kidney glucose + Neurotransmitter dysfunction in the brain 6. Fat lipolysis + H. RELATIONSHIP OF DIABETES-SPECIFIC COMPLICATION Decreased glucose uptake in the muscles 7. Neurotransmitter - AND GLUCOSE TOLERANCE 8. Incretin effect Increased glucose reabsorption in the kidneys Increased lipolysis in the adipose tissues Decreased incretin effect THE TRIUMVIRATE Main definition of diabetes: impaired insulin secretion, impaired insulin action, or both ○ Acts on the liver and acts on the muscle by way of the insulin receptor ○ If you have a defect either in the amount of insulin produced or in the responses of insulin sensitive organs → diabetes Hyperglycemia due to: ○ Pancreas: Too little/abnormal insulin secretion and insulin action (too little) Figure 21. Relationship of Diabetes-Specific Complication and Glucose Tolerance Based on studies, people with diabetes have a reduction or loss of the 2nd phase insulin response ○ Muscle: Decrease glucose uptake YL7: 8 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  ○ Liver: Increased hepatic glucose production ROLE OF FREE FATTY ACIDS HYPERGLYCEMIA Insulin resistance comes from excess hypertrophy of adipose tissue → more FFA released due to lipolysis → FFA will then circulate to the blood circulation and infiltrate liver and muscle ○ Fatty liver: when fat infiltrates the liver ○ Insulin resistant muscle: when lipids infiltrate the muscle Both liver and muscle are supposed to respond to insulin, but since they are resistant, glucose stays in the blood, leading to hyperglycemia ○ Liver increases gluconeogenesis instead of taking up glucose since it does not respond to insulin Further contributes to hyperglycemia Figure 23. The Triumvirate INSULIN SECRETION IMPAIRMENT Patients with T2DM: loss of 1st phase insulin response leads to a much lower 2nd phase response and happens at a later period of time → high sugar ○ 1st phase insulin response: most important controller of blood sugar within the first 5 minutes Figure 26. Role of Free Fatty Acid Hyperglycemia INCRETIN IN GLUCOSE HOMEOSTASIS GLP-1 and GIP are synthesized and secreted from the gut in response to food intake Incretins are hormones that are important for glucose metabolism Released from the gut, secreted by the ileum and Figure 24. Phases of Insulin Response jejunum Incretins: GLP-1 and GIP — L cell in the ileum: secrete proglucagon that eventually becomes GLP-1 — K cell in the jejunum: secrete GIP After you eat a meal, your gut will release the incretins, which will go to circulation where it will stimulate insulin secretion in beta cell and suppress glucagon in alpha cells ○ Release of incretin normalizes blood sugar by increasing insulin and decreasing in glucagon secretion ○ This is why GLP-1 receptor agonist can improve insulin secretion and lower glucagon to normalize sugar levels Figure 25. β-Cell Loss Over Time FIGURE 25 The UKPDS showed that people with diabetes continue to have reduction in beta cell mass T2DM etiology is insulin resistance ○ Insulin resistance progressively kills beta cell due to the following: Hyperglycemia → contribute to glucotoxicity High lipids → contribute to lipotoxicity (e.g. obesity) Figure 27. Incretin in Glucose Homeostasis ○ Both the glucotoxicity and lipotoxicity contribute to the death of the beta cells YL7: 9 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  Figure 28. Incretin in Homeostasis Figure 30. GLP-1 Degradation by DPP-4 NICE! ABNORMAL INSULIN AND GLUCOSE DYNAMICS New incretin based medicines are going to be released soon Islet of Langerhan: important hormones includes insulin and Ozempic: GLP-1 receptor agonist glucagon ○ One of the most famous medicines that was hyped in Relationship of insulin to glucagon social media ○ Blue line: normal individual ○ Very good drug for diabetes After we eat a meal, insulin will increase in first and ○ Endorsed by Elon Musk second phase He lost a lot of weight because he injected Ozempic Glucagon goes down after you eat because it is a (Semaglutide) counterregulatory hormone Worldwide shortage of ozempic ○ Red line: person with diabetes — Patients with diabetes are affected since people with Low insulin secretion obesity without diabetes use it No first phase insulin secretion — We are trying to educate people that Ozempic should Glucagon goes up instead of going down not be used if you do not have diabetes — Opposite effect of insulin → Increases sugar — If the main intention is for weight loss, there are other Net effect: excessive hyperglycemia GLP-1 receptor agonist that may be used Major mechanism why diabetes happens: high glucagon, low Reserve Ozempic for people with diabetes insulin further increasing both fasting and postprandial because as of now there is low supply around the blood sugar world ○ Doc’s patients prescribed with Ozempic have a hard time procuring the medicine since it goes out of stock quickly GLP-1 AND GIP RESPONSES IN TYPE 2 DIABETES Orange line: people with diabetes have very low GLP-1 levels ○ Injecting GLP-1 receptor agonist may increase GLP-1 level of patient, which will improve their sugar ○ How to increase GLP-1 Recall: GLP-1 is a protein degraded by the enzyme dipeptidyl-peptidase-4 (DPP-4) — DPP-4 inhibitors: used to improve GLP-1 level in your blood Figure 31. Abnormal Insulin and Glucagon Dynamics Oral drug that is available in the country Inhibit the DPP-4 means you have more active INCREASED GLUCOSE REABSORPTION IN KIDNEYS biological GLP-1 and can hopefully control the blood sugar levels Recall: kidneys filter, including glucose through the glomerulus Proximal convoluted tubule: 90% of glucose reabsorption ○ Mediated by SGLT-2, a transporter Remaining 10%: Mediated by SGLT-1 Normally, urine should not have any sugar at all because almost 100% have been reabsorbed by the SGLT2 and SGLT1 at the level of the proximal convoluted tubule Figure 29. GLP-1 and GIP responses in T2DM YL7: 10 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  SGLT-2 inhibitors → inhibit the SGLT-2 from reabsorbing the glucose, leads to excretion of excess sugar in the urine ○ Game-changer → since before if we say we are treating a person’s diabetes, the urine should have no sugar ○ However, the effectivity SGLT-2 inhibitor is indicated by the presence of sugar in the urine A lot of patients ask why their urine has pee Doc will tell them that the medicine is working since they are able to excrete excess sugar in their urine Figure 32. Increased Glucose Reabsorption in the Kidneys Figure 35. Glucose Transporter Levels Figure 33. Transporters Involved in Glucose Reabsorption FIGURE 33 Very important mechanism in controlling the sugar levels Called sodium glucose cotransporter because you need a sodium together with the glucose to enter that particular transporter Figure 36. Renal Glucose Excretion and Reabsorption ○ Glucose can then be reabsorbed back to the blood by passing through the SGLT-2 at the basal membrane of the FIGURE 36 proximal convoluted tubule Normal person threshold: 180-200 mg/dL for kidneys to Good SGLT-2 and SGLT-1: glucose will come from filtered reabsorb sugar urine back to the blood → no hypoglycemia ○ Beyond this, kidneys will excrete extra sugar ○ Kidney can return the sugar filtered by the glomerulus People with diabetes ○ Because you have an overexpression of SGLT2 inhibitors → increased reabsorption threshold → increased excretion threshold → high sugar before it even comes out with urine ACTIVE RECALL BOX 1. T/F A blood glucose concentration of 150 mg/dL is above the glucose reabsorption threshold. 2. T/F 70% of glucose is reabsorbed in the PCT. Figure 34. Threshold for Glucose Absorption in the Kidneys Answers: 1F, 2F FIGURE 34 Certain threshold → kidneys can only reabsorb so much ○ When the level of blood sugar goes beyond 180 to 200 mg/dL, the kidneys will start to spill glucose in the urine → exceeded reabsorption threshold INCREASED GLUCOSE TRANSPORTER PROTEINS Among people with diabetes, SGLT-2 and GLUT-2 are overexpressed ○ Too much SGLT-2 and GLUT-2 means more sugar reabsorbed → even higher sugar YL7: 11 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  J. CENTRAL REGULATION OF APPETITE HYPOTHALAMIC DOPAMINERGIC TONE AND AUTONOMIC IMBALANCE Figure 37. Central Regulation of Appetite FIGURE 37 Figure 39. Autonomic Imbalance in the Brain due to Diabetes The brain has a lot to do with diabetes ○ Our craving for food is controlled by our brain, particularly An important neurotransmitter, dopamine is low in people with the hypothalamus diabetes early in the morning which leads to: ○ The arcuate nucleus contains: ○ Increases sympathetic tone Neuropeptide Y (NPY) and Agouti-Related Protein ○ Increases hepatic gluconeogenesis (AgRP) which increase food intake → become hungry Can lead to hyperglycemia Proopiomelanocortin (POMC) → when activated, ○ Increases insulin resistance causes one to stop eating → which decreases food ○ Increase inflammation and hypercoagulation intake and induces satiety Therefore, the brain is a very important organ when it comes to the development of diabetes ALTERED HYPOTHALAMIC FUNCTION IN RESPONSE TO K. THE EGREGIOUS ELEVEN GLUCOSE INGESTION IN OBESE HUMANS Figure 40. The Egregious Eleven Figure 38. Satiety Transmission of Obese and Lean Patients Stanly Schwartz added to the Ominous Octet and called it the Lack of inhibition in the hypothalamus Egregious Eleven which contribute to the development of It takes a longer period of time, for a person with diabetes to diabetes that include 3 factors not part of the ominous feel full octet: ○ Normally, a person will feel full by 15 minutes, but a ○ Gut microbiota person with diabetes will take 30 minutes to feel full There are certain beneficial bacteria in our gut that can This causes them to eat more before they stop reduce our chances of developing diabetes and even This leads to an increase in blood sugar and obesity obesity ○ Inflammation Another important mechanism that contributes to the development of diabetes ○ Stomach Related in terms of absorption All three factors have one thing in common → you will not develop hyperglycemia unless they all lead to insulin deficiency ○ The final common pathway of the different pathogenetic processes is low insulin secretion ○ You will not have diabetes as long as you produce sufficient natural insulin YL7: 12 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  L. COMPLICATIONS OF DIABETES Remember, the two leading causes of death in the Philippines are ischemic heart diseases and stroke which are common macrovascular complications of diabetes FACTORS PROMOTING DIABETES COMPLICATIONS Figure 41. Complications of Diabetes If you continue to have hyperglycemia, you can develop complications that can either be acute or chronic Acute: Quickly develop from hours to days ○ Presents emergencies such as diabetic ketoacidosis, hyperosmolar hyperglycemic states, and hypoglycemia (possible complication of treatment) Chronic: Will take months to years Figure 44. Contributing factors to diabetes ○ Can either be small vessel disease or large vessel disease The complications of diabetes are not just due to blood sugar but are also due to hyperglycemia, hypertension, dyslipidemia, and insulin resistance ○ All of these can happen over a period of time When treating a person with diabetes, you do not only focus on the blood sugar, but also correct the other factors present that can lead to complications ○ Not easy to prescribe medications to patients with diabetes, since you have to consider a lot of pharmacologic options, and monitor a lot of factors Figure 42. Chronic Complications Under the small vessel complications, these include: M. MANAGEMENT AND TREATMENT ○ Retinopathy - Eyes ○ Nephropathy - Kidney ○ Neuropathy - Nerves The complications that kill people with diabetes are macrovascular complications ○ Cerebrovascular accident (Stroke) ○ Coronary artery disease ○ Peripheral artery disease → very common cause of amputation among patients with diabetes Figure 45. Rate of Complications and Blood Sugar Levels If you persist to have elevated sugar, there is an almost linear relationship in the development of complications Your goal is to bring down the sugar of the person to ideal levels Figure 43. Effects of Complications All of the complications can be present in the same individual The macrovascular complications can immediately kill a person ○ Heart attack ○ Stroke The microvascular complications can reduce the quality of life ○ Blindness ○ Amputation Figure 46. Incidence Rates for Myocardial Infarction and Microvascular Complications by Updated Mean Haemoglobin A1c Concentration YL7: 13 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  GLYCEMIC GOALS FOR ADULTS WITH DIABETES FIGURE 46 Study by the UKPDS People with newly diagnosed diabetes can have a reduction in the complications if their HbA1c is brought to less than 7% In patients with diabetes, the study shows a very strong correlation of the following with higher HbA1c: ○ Increasing risk of heart attack ○ Increasing risk of microvascular complications The lower the HbA1c, which is a marker of chronic hyperglycemia, the lower the risk of complications among patients with T2DM Figure 49. Glycemic goals for adults with DM To reduce complications: PREVENTING COMPLICATIONS ○ HbA1c must be less than 7% ○ Precapillary blood glucose must be between 80 and 130 mg/dl ○ Postprandial blood glucose must be less than 180 mg/dl Figure 47. Approach to Preventing Complications When you treat a person, you must look at their sugar, and other risk factors such as blood pressure and cholesterol, as well as weight in order to protect their heart and kidneys. Figure 50. Approach to Management of Hyperglycemia Target does not always have to be < 7% → it is a moving target HbA1c target can be lower than 7% in cases of: ○ Newly diagnosed ○ Long life expectancy ○ No complications ○ Has a lot of resources If a patient has complications such as cancer, already had a stroke, is bedridden, on an NGT, HbA1c can be higher than 7%, such as between 7-8% ○ Applicable to the frail elderly Figure 48. Goals of Care in DM N. ESSENTIAL ELEMENTS IN COMPREHENSIVE CARE OF These are the factors (Figure 48) that are important to talk T2DM about. When treating a patient with diabetes, the main goal is to avoid complications to improve their quality of life ○ These entail taking into consideration factors such as shared decision making and choosing the treatment that is most ideal for the needs of the patient Figure 51. Algorithm for Comprehensive Management of T2DM Blood sugar can be controlled via dietary intervention, increased physical activity, and medication YL7: 14 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  Important to treat other comorbid conditions O. HOLISTIC PERSON-CENTERED APPROACH TO T2DM MANAGEMENT OF DM MANAGEMENT Healthy Lifestyle Weight management Medical nutrition therapy Increased physical activity Pharmacologic Oral agents Injectable agents → not just insulin ○ Non-insulin E.g. GLP-1 receptor agonists ○ Insulin PRINCIPLES OF PHARMACOLOGIC TREATMENT OF T2DM Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c ○ For example, if you have a patient with obesity, consider Figure 53. Holistic person-centered approach to T2DM that they may have insulin resistance in their adipose tissues. In holistic care, we want to make sure that we control This can help with decision-making everything and we engage the patient in the aspects of Will require multiple drugs in combination to correct multiple treatment of diabetes pathophysiologic defects ○ Patient may have more than one pathogenic problem QUICK REVIEW Must be started early in the natural history of T2DM, if QUESTION progressive Beta-cell dysfunction is to be prevented ○ Be aggressive with treatment 1. Monosaccharides are absorbed in the ileum of the small intestine. Once in the blood, glucose travels to the portal vein. TARGETED TREATMENT FOR MEDIATING PATHWAYS FOR a. Only the first statement is true. HYPERGLYCEMIA b. Only the second statement is true. c. Both statements are true. d. Both statements are false. 2. Which association is correct? a. Alpha cells: Insulin b. Beta cells: Glucagon c. Delta cells: Insulin d. F cells: Pancreatic polypeptide 3. Which of the following is a sign of insulin resistance? a. Obesity b. Acanthosis nigricans c. Polydipsia d. Ketonuria 4. Which of the following choices can normalize blood sugar by increasing insulin and decreasing glucagon secretion? Figure 52. Targeted Treatment for Mediating Pathways for Hyperglycemia a. Incretin If the abnormality is in the liver, you can give Metformin or a b. Neurotransmitters Thialozidinedione such as Pioglitazone c. Hepatic glucose production If the abnormality is in the muscle or adipose, you can give d. Increased glucose uptake Thialozidinediones first 5. Which of the following is NOT part of the ominous octet? If the abnormality is in the kidney, SGLT-2 inhibitors can be a. Decreased glucagon secretion given b. Impaired insulin secretion If the abnormality is in the pancreas, insulin, incretins or c. Decreased hepatic glucose production GLP-1 receptor agonists can be given d. Neurotransmitter dysfunction Some of these are not available readily in the Philippines, but 6. In which phase of the pathophysiology of type 1 diabetes are possible agents for treatment based on the pathogenic does the stabilization of β-cell population occur after an initial mechanisms decline? ○ Can give more than one treatment a. Epitope spreading b. Honeymoon phase c. Choice d. Choice 7. Which of the following influenced the cut-offs for diagnosis of diabetes? a. Risk of developing retinopathy b. Risk of developing hypertension YL7: 15 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16  c. Risk of developing peripheral neuropathy d. Risk of developing fatty liver 8. Which is the strongest predictor for diabetes? a. Polyuria b. Unexplained weight loss c. Polydipsia d. Polyphagia 9. Which of the following is true about insulin resistance? a. Increased glucose uptake b. Decreased protein breakdown c. Increased lipolysis d. Increased amino acid uptake 10. The HbA1c target does not always have to be < 7%. a. True b. False Answer Key 1B, 2D, 3B, 4A, 5C, 6B, 7A, 8C, 9C, 10A RATIONALE 1. B. Only the second statement is true – Monosaccharides are absorbed in the jejunum, not the ileum 2. D. F cells: Pancreatic polypeptide – Alpha cells (glucagon), Beta cells (insulin), Delta cells (somatostatin) 3. B. Acanthosis nigricans – Obesity can cause insulin resistance, but acanthosis nigricans are hyperpigmented, thickened skin folds that are a sign of insulin resistance 4. A. Incretin – Release of incretin normalizes blood sugar by increasing insulin and decreasing in glucagon secretion 5. C. Decreased hepatic glucose production – Increased hepatic glucose production is part of the ominous octet 6. B. Honeymoon phase – It is where β-cell population stabilizes, the decline tends to plateau, and blood sugar remains stable. 7. A. Risk of developing retinopathy – By the time your FPG, 2-h PG, and HbA1c reach the levels of the cut-offs, there is a rapid rise in the chance that you will develop retinopathy → they used these cut-offs to diagnose diabetes due to the development of complications 8. C. Polydipsia – The strongest predictor of risk for diabetes is polydipsia. 9. C. Increased lipolysis – The other choices correspond to normal insulin action. In normal insulin secretion, there is decreased lipolysis. 10. A. True – It is a moving target. REFERENCES REQUIRED Nicodemus, N.J. (2023, September 26). Adult Hyperglycemia and Hypoglycemia. [Lecture slides]. IMPORTANT LINKS Feedback form: https://bit.ly/2026TF Errata tracker: https://bit.ly/2026ET FREEDOM SPACE YL7: 16 of Adult Diabetes Mellitus and Hyperglycemic Disorders 05.09a 16 Module 05: Endocrine [Clinical Medicine] Hypoglycemic Disorders Nemencio A. Nicodemus Jr., MD| September 26, 2023 TABLE OF CONTENTS LEARNING OBJECTIVE I. DEFINITION OF CLINICAL HYPOGLYCEMIA II. SYMPTOMS OF HYPOGLYCEMIA A. CLASSIFICATION OF SYMPTOMS B. SYMPTOMS III. PHYSIOLOGIC RESPONSES TO DECREASING PLASMA GLUCOSE CONCENTRATION A. PHYSIOLOGIC EVENTS B. BODY’S RESPONSE C. MECHANISMS THAT PREVENT HYPOGLYCEMIA IV. CAUSES OF HYPOGLYCEMIA IN ADULTS A. IN ILL OR MEDICATED ADULTS B. IN SEEMINGLY WELL INDIVIDUALS V. APPROACH TO PATIENTS WITH HYPOGLYCEMIA (WITHOUT DIABETES) A. REVIEW HISTORY, PHYSICAL FINDINGS, Figure 1. Sympathetic Chain and Adrenal Medulla Interaction LABORATORY DATA Table 1. Symptoms of Hypoglycemia B. WORK UPS Autonomic Neuroglycopenic C. RECREATE CIRCUMSTANCES (Neurogenic) (Effects on the brain due to D. PROCEDURES FOR LOCALIZING INSULINOMA deprivation of glucose) E. TAILOR TREATMENT Palpitations Weakness VI. HYPOGLYCEMIA IN DIABETES Tremor Drowsiness A. DEFINITION Anxiety/arousal Impaired cognition (difficulty B. EFFECTS OF HYPOGLYCEMIA concentrating, confusion) C. CONVENTIONAL RISK FACTORS FOR Sweating Incoordination Hunger Behavioral changes HYPOGLYCEMIA IN DIABETES Paresthesias D. CLASSIFICATION OF HYPOGLYCEMIA IN DIABETES E. CONFIRMATION OF HYPOGLYCEMIA: TAKE NOTE! WHIPPLE’S TRIAD When you consider hypoglycemia as a differential, the VII. QUICK REVIEW symptoms in Table 1 are what you will try to observe and ask VIII. REFERENCE about A. REQUIRED IX. FREEDOM SPACE B. SYMPTOMS LEARNING OBJECTIVE BODY’S RESPONSE TO PROGRESSIVELY LOWER BLOOD GLUCOSE CONCENTRATION Discuss the presentation, approach to the differential diagnoses, and management of hypoglycemia Manifestations don’t occur all at the same time because some occur at specific levels of the sugar I. DEFINITION OF CLINICAL HYPOGLYCEMIA Subtle sign: you feel hungry Clinical condition = you can see it ○ This is can be the first thing you feel but it’s normal A plasma glucose concentration low enough to cause ○ Starts to happen when blood sugar goes down to around 60 symptoms and/or signs, including impaired brain functioning mg/dL (if you don’t have diabetes) ○ Recall: the brain is very much dependent on glucose for ○ Body will release glucagon, epinephrine, and cortisol to energy counteract hypoglycemia → adrenals will start to function ○ When you have low glucose, one of the first organs to be ○ If you still haven’t eaten and just allowed this to happen, affected is the brain you can develop cold sweats and tremors Especially if the blood glucose levels will be very low NICE! II. SYMPTOMS OF HYPOGLYCEMIA In Doc’s experience after an exam around lunch time, he felt A. CLASSIFICATION OF SYMPTOMS blurred vision, tremors, and cold sweats → hypoglycemia ○ He ran to the canteen to eat immediately Neuroglycopenic ○ Scary to feel that you could collapse at any time due to ○ The result of brain glucose deprivation per se hypoglycemia Neurogenic or Autonomic ○ He has no diabetes and was not on medication → it may ○ Largely the result of the perception of physiological happen to a normal person changes caused by the sympatho-adrenal discharge (triggered by hypoglycemia) Blood sugar