Essentials of Endocrinology and Metabolism: A Practical Guide for Medical Students [1st ed.] 9783030395711, 9783030395728

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Essentials of Endocrinology and Metabolism A Practical Guide for Medical Students Fredric E. Wondisford

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Essentials of Endocrinology and Metabolism

Fredric E. Wondisford

Essentials of Endocrinology and Metabolism A Practical Guide for Medical Students

Fredric E. Wondisford Department of Medicine Robert Wood Johnson Medical School New Brunswick, NJ USA

ISBN 978-3-030-39571-1    ISBN 978-3-030-39572-8 (eBook) https://doi.org/10.1007/978-3-030-39572-8 © Springer Nature Switzerland AG 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

I wrote this book as a resource for students interested in learning medical endocrinology at the mechanistic level. Despite a number of excellent biochemistry, physiology, and medical science textbooks, none in my opinion achieve the correct balance for this purpose, being either too comprehensive or too limited in scope. My hope is that this text achieves the correct balance. Experience is the best teacher, and so it is with this book. Jeffery Flier and I first developed an endocrinology course for students in the Harvard-MIT Program in Health Sciences and Technology, and this structure can be seen in many of the chapters. Roy Weiss helped me refine the content to some degree when I delivered the material to medical students at the University of Chicago. When I left Chicago for Johns Hopkins University School of Medicine, I had the opportunity to develop an expanded course in the new Genes to Society curriculum. I am extremely grateful to Doug Ball, David Cooke, Hank Fessler, Marc Halushka, Mehboob Hussain, Sally Radovick, and Aniket Sidhaye for helping me to develop this course. The book you are about to read is a composite from all these experiences. Beyond help from outstanding colleagues, exposure to bright and energetic students was equally critical in shaping the content of this book. What worked and what didn’t are frequently measured by the students’ performance on exams and standardized tests, but equally important to me was whether the students liked the course content and delivery. Refinement on both these fronts was only possible through student feedback, and I want to thank all of my past students for their help. This book would not have been possible without the support and critique of my family. My daughters, Sarah and Anne, are both in medicine and have had to suffer through many of my teaching moments. I suppose they were my first students; and some of this endocrinology material, I must confess, was first presented to them. Finally, the person who deserves the most credit for helping me put this book together is my spouse, Sally Radovick. She and I are both academic endocrinologists and frequently compare teaching notes, among many other things. New Brunswick, NJ, USA

Fredric E. Wondisford

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Contents

1 Introduction to Endocrinology Concepts������������������������������������������������   1 Part I Diabetes 2 Getting Prepared Series for Diabetes������������������������������������������������������   9 3 Diabetes Types and Diagnosis ������������������������������������������������������������������  23 4 Diabetes Complications ����������������������������������������������������������������������������  31 5 Diabetes Pharmacology ����������������������������������������������������������������������������  39 6 Diabetes Cases��������������������������������������������������������������������������������������������  45 Part II Thyroid 7 Getting Prepared Series for Thyroid��������������������������������������������������������  55 8 Abnormal Thyroid Function��������������������������������������������������������������������  65 9 Thyroid Testing������������������������������������������������������������������������������������������  77 10 Thyroid Pharmacology������������������������������������������������������������������������������  89 11 Thyroid Nodules and Cancer��������������������������������������������������������������������  93 12 Thyroid Cases�������������������������������������������������������������������������������������������� 103 Part III Calcium 13 Getting Prepared Series for Calcium ������������������������������������������������������ 115 14 Hypercalcemia�������������������������������������������������������������������������������������������� 125 15 Hypocalcemia �������������������������������������������������������������������������������������������� 133

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viii

Contents

16 Calcium Pharmacology ���������������������������������������������������������������������������� 141 17 Calcium Cases�������������������������������������������������������������������������������������������� 149 Part IV Adrenal 18 Getting Prepared Series for Adrenal�������������������������������������������������������� 159 19 Adrenal Cortex������������������������������������������������������������������������������������������ 169 20 Adrenal Testing������������������������������������������������������������������������������������������ 177 21 Adrenal Pharmacology������������������������������������������������������������������������������ 183 22 Secondary Hypertension �������������������������������������������������������������������������� 191 23 Adrenal Cases�������������������������������������������������������������������������������������������� 197 Part V Hypothalamus and Pituitary 24 Getting Prepared Series for Pituitary������������������������������������������������������ 211 25 Prolactin������������������������������������������������������������������������������������������������������ 221 26 Growth Hormone �������������������������������������������������������������������������������������� 229 27 Reproductive Function������������������������������������������������������������������������������ 241 28 Posterior Pituitary������������������������������������������������������������������������������������� 259 29 Pituitary Cases ������������������������������������������������������������������������������������������ 271 30 Puberty Cases �������������������������������������������������������������������������������������������� 279 Index ������������������������������������������������������������������������������������������������������������������ 289

1

Introduction to Endocrinology Concepts

Objectives

• Understand the definition of endocrinology • Be able to classify hormones • Define free versus bound hormone

Given that hormone means “to set in motion” (from Greek), we start here with this definition. Endocrine glands are ductless, and their products (hormones) circulate in the blood to act at a distant site. Exocrine glands contain ducts and secrete substances into the gut lumen or on the skin. In fact, the pancreas is the only gland that has both exocrine and endocrine parts. By mass, more than 98% of the pancreas is exocrine; the remaining 2% of the pancreatic mass is endocrine (islet of Langerhans). Endocrine glands are ductless, although during development some glands are connected to the parent structure by a duct (e.g., thyroid and pancreas), which subsequently degenerates. Endocrine action is distinguished from paracrine and autocrine action because endocrine hormones must travel in the blood (Fig. 1.1). Hormones can also act in a local or paracrine fashion by diffusing in the interstitial fluid or can act on the cell of origin in an autocrine fashion. There are seven classic endocrine glands: hypothalamus, pituitary, thyroid, parathyroid, pancreas, adrenal, and gonad. Some authors include the pineal gland (melatonin), but we will not for the purposes of this book. Four of these glands have two discrete endocrine parts or functions: hypothalamus, pituitary, thyroid, and adrenal. The hypothalamus has both magnocellular (large) and parvocellular (small) neurons. The former synthesize antidiuretic hormone (ADH) and oxytocin, which are then transported to the posterior pituitary for secretion. The latter secrete hormones into the portal circulation, which are then transported to the anterior pituitary. Most of the thyroid is made up of follicles; but C-cells, which synthesize calcitonin and © Springer Nature Switzerland AG 2020 F. E. Wondisford, Essentials of Endocrinology and Metabolism, https://doi.org/10.1007/978-3-030-39572-8_1

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1  Introduction to Endocrinology Concepts

Fig. 1.1  Types of cellular communication

Gland

Target

Endocrine

Paracrine

Autocrine

are neural crest derivatives, migrate to the thyroid as parafollicular cells (although recent work suggests they may be of endothelial origin). The adrenal cortex is derived from mesoderm and makes steroid hormones, while the medulla is of neural crest origin and makes E and NE. As noted above, the pancreas has both exocrine and endocrine parts, and the gonad contains both an endocrine part and germ cells needed for reproduction. There are three recognized hormone classes: tyrosine, peptide, and steroid hormones. You have learned about catecholamines in the past (DA, NE, and E), which are all derived from the amino acid tyrosine (Fig. 1.2). You may not be aware that thyroid hormones (T4 and T3) are also derivatives of tyrosine. Catecholamines act by binding to cell membrane receptors, while thyroid hormones act in the nucleus in much the same way that steroid hormones function. The peptide class (Fig.  1.3) includes small molecules (e.g., TRH, GHRH, and ADH) but also larger proteins (e.g., insulin and GH) and heterodimeric proteins containing two discrete subunits (e.g., TSH, LH, FSH, and CG). Peptide hormones are synthesized in the rough ER as prepropeptides. The pre or leader sequence is required to get the peptide inside the ER lumen. All peptide hormones must have a leader peptide, or they cannot be secreted from the cell. The leader sequence is then cleaved in the rough ER lumen yielding the propeptide, which is further processed in the Golgi to remove the C or connecting peptide in the case of insulin. Other propeptides are processed in different ways. Finally, the steroid hormone, a class of hormones (Fig. 1.4), is derived from the polar molecule cholesterol. For steroid hormones, it is worth remembering the 3, 11, 17, and 21 positions, since these carbons are modified during hormone synthesis. Vitamin D is a somewhat unique hormone because the B ring of cholesterol is cleaved by UV light to yield this hormone.

1  Introduction to Endocrinology Concepts

3 COOH

HO

Tyrosine Tyrosine hydroxylase (TH)

CH2CHNH2

HO

L-Dihydroxyphenylalanine (dopa)

COOH

HO

HO

Dopamine (β-hydroxylase (DBH)

CH2CH2NH2 HO

I

HO

NH2

O

HO

Norepinephrine (NE)

I

I

CHCH2NH2

HO

CHCH2NHCH3 OH

Fig. 1.2  Hormones derived from tyrosine Phe

C-terminal amide

N-terminal pyroglutamate

Tyr pGlu

His

Trp

Ser

Tyr

Gly

Leu

Arg

Pro

Gly

Gln

ADH

NH2 Cys

GNRH

Asp Cys

H2N-Phe

Pro

GH 53 S

S 165

Arg

Gly

189 Phe191-COOH 182 S S

TRH Proline O

N H

O Pyroglutamate (5-oxo-proline)

H N

O NH2

N

Insulin S

O N

NH

Histidine

Fig. 1.3  Peptide and protein hormones

α

S

S S

β

S S

O OH

I Triiodothyronine (T3)

HO

Epinephrine (E)

OH

CH2 CH C

OH

Phentolamine N-methyltransferase (PNMT)

O

CH2 CH C

I I Thyroxine, or tetraiodothyronine (T4)

HO

Dopamine (DA)

NH2

O

HO Dopa decarboxylase

I

I

CH2CNH2

TSH

4

1  Introduction to Endocrinology Concepts Hormone classes

Steroids - all derived from cholesterol CH2OH OH CH3

O

CH3

C HO

O OH

CH3

HO

HO

O

Estradiol

DHEA

Cortisol CH2OH O

OH CH3

HO

HC

C

OH

O

CH3

O

O

OH Testosterone

Aldosterone

OH 1,25 VitD

Fig. 1.4  Steroid hormones

Amines (short for catecholamines) and peptide hormones are not protein bound in the circulation and for this reason have a short half-life and a pulsatile hormone secretory pattern. An exception is IGF-1, which mediates much of growth and has its own binding proteins (IGFBPs). Thyroid hormones and steroid hormones, in contrast, are heavily bound to serum transport proteins. They have a long half-life and don’t exhibit a pulsatile secretory pattern. However, they do exhibit a circadian secretory pattern even though they are heavily protein bound. Concept Check 1

• Which of the following is not a hormone class? A. Tyrosine B. Peptide C. Steroid D. Phenylalanine Corticosteroid-binding protein (CBG) transports cortisol, progesterone, and aldosterone. Sex hormone-binding globulin (SHBG) transports testosterone, dihydrotestosterone (DHT), and estrogens. A more important concept to remember is that androgen affinity to SHBG is higher than estrogen affinity. The adrenalspecific androgen precursors (androstenedione and DHEAS) are not bound to

1  Introduction to Endocrinology Concepts Fig. 1.5  Free versus bound hormone

5 Hormone transport Target tissue

Free hormone

Bound hormone

SHBG. Thyroxine-binding globulin (TBG) transports T4 and T3. Albumin transports less specifically (lower affinity) all steroid and thyroid hormones. In general, all serum hormone transport proteins (except albumin) are increased by estrogen and pregnancy (both increase synthesis) and decreased by cirrhosis (lower synthesis) and nephrotic syndrome (protein loss). The free hormone (i.e., the fraction of hormone not bound to transport proteins) is the active fraction (Fig. 1.5). The body attempts to maintain the free hormone concentration but not necessarily the total hormone concentration. It does so using a classic negative feedback system. A commonly used analogy is your heating system at home. When the temperature is low (free hormone low), the furnace cycles on to increase heat production and raise the temperature to the set point (normal free hormone concentration). The set point of the system is determined by the thermostat in the same way that the body has sensors to determine the set point of many physiological systems (e.g., body temperature and blood pressure). Conversely, if the temperature is above the set point, the furnace shuts off. Remember, the thermostat is only concerned about the temperature (free hormone); it has no idea about the furnace’s heat production capacity (total hormone). Concept Check 2

• The body precisely controls the serum ___________ hormone level. A. Total B. Bound C. Free Frequently students confuse stimulation of a pathway with positive feedback. These are not the same. While stimulation of a pathway is necessary in a positive feedback loop, an ever-increasing positive stimulation is also required for positive

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1  Introduction to Endocrinology Concepts

Table 1.1  Estimated prevalence of endocrine diseases in the USA Obesity Type 2 diabetes Hyperlipidemia Hypothyroidism Graves’ disease Thyroid nodules Osteoporosis Hyperparathyroidism Vitamin D deficiency Polycystic ovary syndrome

>30% >8% >25% 7% F, 1% M 2% F, 0.1% M 5% palpable, >25% by ultrasound 10% F, 5% M 0.20% 40% 10%

feedback. Think about the microphone squeal on a PA system: This is positive feedback. Examples of positive feedback loops are found in immunology, during ovulation, and in labor and delivery. Endocrine disease can be broadly grouped into three categories: hypofunction, hyperfunction, and hormone resistance. When viewed together, endocrine diseases are also quite prevalent in the USA as indicated (Table 1.1). Concept Check Answer Key

• Concept Check 1: D • Concept Check 2: C

Part I Diabetes

2

Getting Prepared Series for Diabetes

Objectives

• • • •

Review pancreatic anatomy relevant to diabetes mellitus Understand how blood glucose is maintained in the normal range Review insulin and glucagon action Learn the location and regulation of various subtypes of glucose transporters (GLUTs) • Learn the location and kinetic differences between hexokinase and glucokinase • Review factors that promote insulin secretion from the pancreatic β-cell The pancreas is retroperitoneal and has three distinct parts: head, body, and tail (Fig. 2.1). The body and tail are located at L1, and the head is located at L2 within the C-curve of the duodenum. Most of the pancreatic mass is composed of exocrine cells that are clustered in lobules as acini, which drain into the pancreatic duct and then into the duodenum. Embedded within the acini are richly vascularized clusters of endocrine cells called the islets of Langerhans (Fig. 2.2). Most of the islet is made up of β-cells, which secrete insulin. Approximately 20% of the cells are alpha cells, which secrete glucagon. A small number of delta cells secrete somatostatin (SS), and an even smaller number of cells secrete pancreatic polypeptide. The arterial blood supply to the pancreas is derived from the splenic artery and the superior (from celiac trunk) and inferior (from SMA) pancreaticoduodenal arteries. Although islets represent only 2% of the mass of the pancreas, they receive approximately 10%–15% of the pancreatic blood flow through many fenestrated capillaries. Venous blood from the pancreas drains into the hepatic portal vein. The liver then receives the highest concentration of insulin. Most of the pancreas is derived from the dorsal pancreatic bud (Fig. 2.3a). The ventral bud and bile duct rotate around and join with the dorsal bud (Fig. 2.3b). Note © Springer Nature Switzerland AG 2020 F. E. Wondisford, Essentials of Endocrinology and Metabolism, https://doi.org/10.1007/978-3-030-39572-8_2

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2  Getting Prepared Series for Diabetes

Right suprarenal gland

Spleen

Bile duct

Pancreas

L1

Gallbladder Duodenum superior part

L2

Duodenum -ascending part

Duodenum -descending part

L3

Descending colon

Duodenum -inferior part

Ascending colon

Fig. 2.1  Abdominal anatomy relevant to the pancreas

a

b Exocrine pancreas Beta cell

Delta cell Alpha cell

Islet

Fig. 2.2  Pancreas histology

Capillaries

2  Getting Prepared Series for Diabetes

a

11

Stomach

Bile duct Bifid ventral pancreatic bud

b

Dorsal pancreatic bud Bile duct

c BIle duct (passing dorsal to duodenum and pancreas)

Duodenum Anular pancreas Site of duodenal obstruction

Fig. 2.3  Development of the normal (a and b) and annular pancreas (c). (Adapted from Moore, Persaud (eds). The Developing Human. 8th ed. Elsevier; 2008. With permission from Elsevier)

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2  Getting Prepared Series for Diabetes

that the bile duct initially attaches to the ventral aspect of the duodenum and is carried around to the dorsal aspect as the duodenum rotates. The main pancreatic duct is formed by the union of the distal part of the dorsal pancreatic duct with the ventral pancreatic duct. The main pancreatic duct or duct of Wirsung empties into the duodenum via the ampulla of Vater. The proximal part of the dorsal pancreatic duct usually obliterates, but it may persist as an accessory pancreatic duct (duct of Santorini). Defects in development result in an accessory pancreas – a pancreas in an ectopic location in the stomach or intestine or annular pancreas, which is found in Down syndrome and results from the growth of a bifid ventral pancreatic bud around the duodenum (Fig. 2.3c). The endocrine pancreas (islets), which is only 1% of the total mass of the pancreas, develops from cells that pinch off from pancreatic ducts. Blood glucose must be maintained in a narrow range to primarily provide energy to the brain. The brain is unable to perform β-oxidation of fatty acids (FAs), so fat is not directly used as a fuel source in the brain. You will see later that in prolonged fasts, ketone bodies can be used as a fuel source, but they are generated from β-oxidation and ketogenesis in the liver. The lower limit of a normal fasting plasma glucose concentration is approximately 70 mg/dL (3.9 mM), but substantially lower glucose levels can occur without any apparent neurologic sequelae. In the USA, we still report blood glucose in mg/dl; but worldwide, mM is more commonly used. Glucose levels 30 yr

LADA

T2DM

Table 3.2  Diagnostic criteria for diabetes mellitus Prediabetes: Increased risk for developing DM Impaired fasting glucose (IFG) – FPG 100–125 mg/dl (5.6–6.9 mM) Impaired glucose tolerance (IGT) – FPG 140–199 mg/dl (7.8–11.1 mM) 2h after an oral glucose tolerance test (75 g) Diabetes mellitus (any of the following) FPG > 126 mg/dl (>7.0 mM) Symptoms of DM plus random plasma glucose concentration >200 mg/dl (>11.1 mM) HbAlc>6.5% Two-hour plasma glucose >200 mg/dl (>11.1 mM) during an oGTT Table 3.3  Correlation of HbA1c and mean plasma glucose levels

HbA1c (%) 6 8 10 12

Mean plasma glucose over previous 3 months 126 mg/dl (7.0 mmol/l) 192 mg/dl (10.2 mmol/l) 241 mg/dl (13.4 mmol/l) 297 mg/dl (16.5 mmol/l)

thinking that it doesn’t matter which type of DM a patient has, but it actually does matter because the treatments are very different. The diagnostic criteria for DM are based on plasma glucose, not whole blood glucose. Prediabetes is a condition at high risk for diabetes, and patients present as impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The latter is based on an oral glucose tolerance test or OGTT where 75 g of glucose is given PO, and the plasma glucose is measured at defined times (Table 3.2). These blood tests should be repeated on a different day before giving someone a diagnosis (exception is a high random glucose with symptoms). Why? Because either prediabetes or DM requires lifelong medical care; and once you get this diagnosis, you are unlikely to ever lose this diagnosis. HgA1c, which is nonenzymatically glycosylated hemoglobin, reflects the mean blood glucose level over the previous few months and is also being used to diagnose DM. A HbA1c of 6.5% or greater is diagnostic of DM and would also meet the FPG criterion for DM (Table 3.3). There is some concern, however, about whether this is a good idea in all

26

3  Diabetes Types and Diagnosis

ethnic groups because the normal ranges appear to be different. This could mean that either normal ranges are different among ethnic groups or that the normal range is the same and certain ethnic groups run higher HgA1c levels that put them at a higher overall risk for complications. While there may be some controversy about the use of HgA1c as a test for DM, the American Diabetes Association has endorsed its use. In contrast, there is no controversy about the use of HgA1c to monitor DM patients. In fact, HgA1c is probably the most reliable single measure of glucose control in DM. The normal range of FPG is based on following people with known FPG levels over time and measuring rates of diabetic complications (retinopathy, nephropathy, and neuropathy). The highest FPG that has no statistical increase in complication risk is considered the upper end of normal, but the range is changing as we observe patients over longer time periods. So one can expect that the FPG criteria for diagnosing DM will change over time. Now we will consider the two main forms of diabetes: T1DM and T2DM. T1DM is an autoimmune disease, which is linked to DR3/DR4 and associated with islet cell autoantibodies such as GAD65, IA-2/ICA-512, and ZNT-8. T1DM is thought to be triggered by viruses, such as coxsackie, rubella, and enterovirus. The genetic predisposition for T1DM is strong (concordance in twins, 40–60%) but not as strong as T2DM, and individuals in Scandinavian countries have the highest incidence of the disease. Overall the incidence of T1DM is slowly rising worldwide. Individuals with a genetic predisposition when exposed to an immunologic trigger (viral infection) initiate an autoimmune process, which results in a gradual decline in mass (Fig. 3.3). This progressive impairment in insulin release results in diabetes when 80% of the β-cell mass is destroyed. Lack of insulin results in muscle and fat wasting. A “honeymoon” phase may be seen in the first 1 or 2 years after the onset of diabetes and is associated with reduced or absent insulin requirements. This is due to recovery of some β-cells after the immunological insult. But just like a “honeymoon” which doesn’t last forever, the disease eventually returns (Fig. 3.3). Table 3.4 summarizes the key findings in T1DM. T2DM like T1DM is a disease caused by both the environment and genetics, but the environmental insult is excess calories, not a viral infection, and the genetic factors are polygenic but not HLA related. The genetic predisposition for T2DM is stronger (concordance in twins, 70–90%) than for T1DM. Reflecting a lack of autoimmunity in this disorder, serum islet autoantibodies are not detected. Overall the incidence of T2DM is much greater than T1DM, which reflects rising incidence in obese populations. South America, Africa, and Asia have some of the greatest increases in incidence rates, which correlate with increasing obesity in these populations. Obese children represent a particularly difficult diagnostic problem as they could either have T1DM or T2DM. Table 3.5 summarizes the key findings in T2DM. The key to understanding T2DM is the insulin resistance induced by obesity. This forces the β-cell to work overtime to make enough insulin. Usually the β-cell becomes dysfunctional (oxidative damage, etc.) and eventually fails after many years. The islet contains islet amyloid polypeptide (IAPP or amylin) deposits in T2DM reflecting excessive insulin synthesis over time (IAPP is also a β-cell product and might be toxic

3  Diabetes Types and Diagnosis

27

Immunologic trigger Immunologic abnormalities Genetic predisposition

Beta cell mass (% of max)

100

Progressive impairment of insulin release Overt diabetes

50

No diabetes Diabetes

A “honeymoon” phase may be seen in the first 1 or 2 years after the onset of diabetes

0 0 (Birth)

Time (years)

Fig. 3.3  Development of T1DM and the “honeymoon” phase. (Adapted from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th ed. www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved) Table 3.4  Summary of type 1 diabetes mellitus

Table 3.5  Summary of type 2 diabetes mellitus

Increasing in incidence worldwide but nothing like T2DM Scandinavian countries are more affected Genetic predisposition based on HLA complex and polygenic HLA DR3 and/or DR4 haplotype >20 additional genetic loci also segregate with T1DM Serum islet cell autoantibodies detectable: GAD65, IA-2/ ICA-512, ZNT-8 Abs can be used to diagnose new-onset/difficult cases Concordance in twins, 40–60% Overall a 5% risk if parent has T1DM or a 10% risk if a sibling has T1DM Viral infections are triggers (coxsackie, rubella, enteroviruses) Everyone but certain ethnic groups are more affected Genetic predisposition is polygenic >20 genetic loci, each conferring a very small risk No serum islet antibodies detectable Concordance in twins, 70–90% Overall a 40% risk if both parents have T2DM Environment causes obesity; genetic background determines whether T2DM results Diagnostic problem in obese children who could have either T1DM or T2DM

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3  Diabetes Types and Diagnosis

to the islet when aggregated as amyloid). Some very obese patients never get T2DM because their β-cell function is extraordinary. Most patients, however, are not so lucky due to a polygenic predisposition, which renders their β-cells less able to adapt. Insulin resistance is not generalized in obese patients, and this is also important in the pathogenesis. The liver, and to a much lesser extent adipose tissue, turns excess calories into fat via the FA synthesis pathway. Excess FAs are stored in the liver and muscle as TAG droplets. Excess storage in adipocytes produces obesity and a lowgrade inflammatory state. Excess TAG storage in the liver and fat causes a selective post-receptor insulin-resistant state in these organs. The chronic inflammatory state in fat also causes insulin resistance in fat and some other organs. Selective insulin resistance elevates blood glucose by blocking movement of GLUT4 receptors to the cell surface and also prevents glycogen storage in both the muscle and liver. T2DM patients actually have low glycogen stores. You might think it is odd that T2DM patients don’t store glucose as glycogen with all the glucose around, but you need insulin action to activate glycogen synthase. Insulin resistance is mostly confined to the PI3K or metabolic branch of intracellular signaling induced by insulin, but not all parts of this pathway are affected (FA and protein synthesis are intact). The mitogenactivated protein kinase (MAPK) branch of insulin signaling is mostly intact, leading to growth of the vasculature and subsequent complications. A graph of the insulin secretory capacity of the β-cell is now shown (Fig. 3.4). Normal glucose tolerance (NGT) is shown as the blue line. As insulin sensitivity decreases, there is normally a logarithmic increase in insulin secretion needed to

1000 Insulin secretion (pmol per min)

As long as β-cells can produce enough insulin, diabetes can be avoided B NGT

C

500 D

IGT

A

Type 2 DM

0 0

50 Insulin sensitivity M value (µmol/min per kg)

100

Fig. 3.4  Insulin secretory capacity of the β-cell. (Adapted from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J. Harrison’s Principles of Internal Medicine, 18th ed. www. accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved)

3  Diabetes Types and Diagnosis Table 3.6  Risk factors for type 2 diabetes mellitus

29

Family history (genetic predisposition) Lifestyle (cause of insulin resistance) Overweight (BMI >25 kg/M2) Physical inactivity Race/ethnicity (high-risk gene pool = Latina, African, Native American, Asian, Pacific Islander) Previous history of: Prediabetes (10%/year progress to T2DM) GDM (40–60% risk in 20 years of T2DM) Cardiovascular disease Hypertension (blood pressure 140/90 mmHg) Low HDL cholesterol (250 mg/dL) Polycystic ovary syndrome or acanthosis nigricans (sign of insulin resistance)

maintain normal plasma glucose levels (A to B transition). This finding also explains why the β-cell is usually limited in its response to obesity and reduced insulin sensitivity. As the β-cell fails, you start to fall off the curve. Prediabetes (IGT) develops first followed by T2DM as the β-cell function further decays. A common misconception by physicians is that T2DM can be cured by weight loss. In fact, β-cell failure is associated with β-cell apoptosis. So if you cure obesity and insulin resistance with weight loss, the islet mass will probably never be completely normal. However, early weight loss during the period of β-cell dysfunction is more likely to be successful in preserving β-cell function. Table 3.6 lists risk factors for T2DM. Most should be obvious to you by now, but some may seem surprising such as CV disease, hypertension, low HDL, and high TAG. The latter risk factors may be due to the fact that diabetes and CV disease are so related that you actually can’t separate one as a risk factor for the other. For example, people with CV disease may have had undiagnosed diabetes for some time. The same can be said for patients with lipid disorders. With that in mind, screening for T2DM is recommended after age 45, earlier if you have risk factors.

4

Diabetes Complications

Objectives

• Understand acute and chronic complications of DM based on their pathophysiologic mechanism. • Understand the most common signs and symptoms of acute and chronic complications of diabetes mellitus. • Explore testing used to diagnose complications in DM patients.

There are two main acute complications in DM: diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS). Both are serious complications and both are associated with significant mortality. In general, DKA is seen in T1DM and an absolute insulin deficiency is required. Some patients with T2DM (African Americans and Hispanics) can also present with DKA. The proposed mechanism relates to the ratio of glucagon to insulin, which must be abnormally high in these T2DM patients even though they still have some circulating insulin levels. In contrast, HHS is seen in older patients with T2DM; HHS causes water and electrolyte loss and results in a very high serum osmolality. Figure 4.1 highlights the differences between DKA and HHS. DKA is primarily a disorder of acidosis and moderate hyperglycemia; HHS is predominantly a severe hyperglycemia with a mild acidosis. Hyperglycemia promotes an osmotic diuresis because the serum glucose exceeds the renal threshold for reabsorption in the proximal tubule. This results in volume depletion, and vasoconstriction and tachycardia are activated to preserve cardiac output. Hyperglycemia independently negatively affects neutrophil and lymphocyte function, and infections are common in patients with DKA.  Infections can also precipitate DKA by increasing insulin resistance. Importantly, the concentration of

© Springer Nature Switzerland AG 2020 F. E. Wondisford, Essentials of Endocrinology and Metabolism, https://doi.org/10.1007/978-3-030-39572-8_4

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4  Diabetes Complications

insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization. This explains why hyperglycemia is seen in both DKA and HHS, but only significant acidosis is seen in DKA. Based on this reasoning, you might be wondering why hyperglycemia is more severe in HHS (i.e., these patients have relatively more insulin action). Most believe that HHS patients present later and lose more fluid than DKA patients precisely because T2DM patients don’t have a significant acid-base disorder. Signs of acidosis include hypotension, Kussmaul respirations, nausea, vomiting, and abdominal pain. In fact, the abdominal complaints of many patients with DKA resolve with treatment of the acidosis. However some patients present with DKA after appendicitis or cholecystitis, so this really makes the diagnosis of an abdominal precipitating event difficult in patients with DKA. Insulin is the brake, and glucagon is the accelerator for ketogenesis and gluconeogenesis. The lack of a brake in DM causes unrestrained lipolysis in fat, which floods the liver with free FA. As you remember FA are broken down to acetyl-CoA, and acetyl-CoA provides sufficient energy to the liver via the TCA cycle (Fig. 4.2).

7.4

DKA

pH

7.3

HHS

KETOACIDOSIS

1500

7.2 1000

7.1 7.0

500

Glucose (mg/dl)

Fig. 4.1 Acute complications of DM: DKA versus HHS

HYPERGLYCEMIA

Fig. 4.2  Keto acid and glucose production in the liver is driven by glucagon

Glycolysis

FFAs from lipolysis

Pyruvate

β-Oxidation

Gluconeogenesis

Oxaloacetate Acetyl-CoA

Ketogenesis

4  Diabetes Complications

33

Excess acetyl-CoA is converted into keto acids (ketone bodies), which are then delivered to the periphery . The excess acetyl-CoA also facilitates gluconeogenesis by blocking pyruvate dehydrogenase (red arrow), which converts pyruvate to acetyl-CoA, and activating pyruvate carboxylase (green arrow), which converts pyruvate to oxaloacetate. Pyruvate and amino acids that are metabolized into pyruvate by the liver come from muscle and are the three carbon substrates for gluconeogenesis. Remember acetyl-CoA facilitates gluconeogenesis but is not a net substrate for glucose production (contrast this with ketogenesis). Glucagon also promotes gluconeogenesis by increasing production of enzymes in this pathway. Treatment considerations of patients with acute complications are listed in Table 4.1.

Concept Check 1

• Which answer denotes correct associations? A. T1DM-DKA; T2DM-DKA B. T1DM-DKA; T2DM-HHS C. T1DM-HHS; T2DM-DKA D. T1DM-HHS; T2DM-HHS

We next look at the chronic complications associated with DM.  They are the main source of morbidity and mortality and are grouped into vascular and nonvascular complications. We won’t spend much time on the nonvascular complications, but they are still important. For example, gastroparesis is a real problem for patients with DM – in severe cases, patients can’t eat without vomiting. Also patients with DM get many unusual infections especially fungal infections (e.g., candidal vaginitis and facial sinus mucormycosis). Vascular complications are either microvascular or macrovascular. Treatment of DM patients reduces microvascular complications; but most treatments have not been shown to reduce macrovascular complications, independently of all of the other treatments that the patient is given for hypertension and hyperlipidemia (except GLP-1 receptor agonists and SGLT inhibitors). Chronic DM complications take time to develop (>10 years). Unlike T1DM patients who tend to present early with ketoacidosis, T2DM patients tend to present Table 4.1  Treatment of acute complications Absolute or relative insulin deficiency: intravenous insulin therapy needed Volume depletion after hyperglycemia-induced osmotic diuresis: replenish volume and electrolytes (i.v. 0.9% NaCl first and then 0.45% NaCl); potassium and phosphate may also need to be repleted Acid-base disorder usually corrects with above therapy. In extreme conditions (pH 6% (20 billion) of total healthcare expenditures in the USA. Measurement of urine microalbumin is the main screening test for early detection of diabetic nephropathy. Microalbuminuria is also a risk factor for cardiovascular disease and usually found after about 10 years of disease; gross proteinuria is observed usually after 15 years of disease. Individuals with diabetic nephropathy very commonly also have retinopathy.

4  Diabetes Complications

35

24

Retinopathy progression, rate

Mean A1C = 11%

10%

20

9%

16 12 8%

8

7%

4 0 0

1

2

3

4

5

6

7

8

9

Length of follow-up, years

Fig. 4.3  The progression of retinopathy in individuals in the DCCT. (Adapted from Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J.  Harrison’s Principles of Internal Medicine, 18th ed: www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.) Fig. 4.4 Diabetic retinopathy: background and proliferative

Background retinopathy Microaneurysms Hemorrhages Cotton wool spots

Proliferative retinopathy Neovascularization

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4  Diabetes Complications

The most sensitive measure for renal disease is measurement of the urine albumin concentration. The cutoff between micro- and macroalbuminuria (aka gross proteinuria) on a spot urine determination is 300mg/g creatinine, which is roughly equal to 300mg/24hr. Dipstick measurements of the urine are less reliable in the microalbumin range but can sometimes give a clue. Annual screening for microalbuminuria begins about 5 years after the diagnosis of T1DM and immediately after the diagnosis of T2DM. Treatment with ACE inhibitors reduces proteinuria probably by dilating the efferent arteriole more than the afferent arteriole of the glomerulus, which then reduces glomerular perfusion pressure. The most common form of diabetic neuropathy is distal symmetric sensory polyneuropathy, which is also known as “stocking and glove” neuropathy. It leads to foot ulcers, infections, and amputations. Mononeuropathy is less common and presents with pain and motor weakness in the distribution of a single nerve (possible vascular etiology). Involvement of CN III is the most common and is associated with diplopia (“down and out pupil”). DM-related autonomic neuropathy can involve multiple systems and causes resting tachycardia, orthostatic hypotension, gastroparesis, hyper-/anidrosis, neurogenic bladder, and impotence. Autonomic neuropathy may also reduce counter-regulatory hormone release (adrenal epinephrine) and sympathetic discharge, leading to hypoglycemic unawareness, which is a very severe and difficult-to-treat complication.

Concept Check 2

• Which of the following is a chronic microvascular complication of DM? A. Peripheral artery disease B. Coronary artery disease C. Cerebrovascular disease D. Retinopathy

In DM patients treated with insulin, hypoglycemia becomes an important consideration. Whipple’s triad is clinically useful for determining symptomatic hypoglycemia. The triad is as follows: (1) symptoms known to be caused by hypoglycemia (hunger, sweating, confusion, seizure, and coma), (2) a low plasma glucose (< 55 mg/dL) at the time of symptoms, and (3) relief of symptoms when the glucose level is raised to normal. Unfortunately, patients with long-standing DM can develop hypoglycemic unawareness, where hypoglycemia damages the brain without generating significant symptoms in the patients. We end with a discussion of macrovascular complications of diabetes such as myocardial infarction (MI), peripheral vascular disease, or stroke. Both the DCCT and UKPDS found no clear benefit of better DM control on reducing macrovascular complications, which seems counterintuitive. For this reason the Look AHEAD (Action for Health in Diabetes) trial was conducted. Actually, the trial was stopped early because no benefit of weight loss (also associated with lower HbA1c levels)

4  Diabetes Complications

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was found versus the conventionally treated patients in reducing death from cardiovascular diseases, nonfatal MIs and strokes, or hospitalizations for angina. These results were unexpected but show the importance of continuing to evaluate time-­ consuming and expensive interventions in DM patients for efficacy and cost-effectiveness. Concept Check Answer Key

• Concept Check 1: B • Concept Check 2: D

5

Diabetes Pharmacology

Objectives

• Understand the different treatment options for patients with diabetes mellitus. • Explore the mechanisms of action of different antidiabetic drugs. • Understand the different types of insulin treatment used to achieve physiologic insulin levels.

The treatment goals of all patients with DM are listed in Table 5.1. These are merely guidelines because certain patients need tighter glucose control (e.g., pregnant) and certain patients need looser glucose control (e.g., elderly). The treatment goals for gestational diabetes mellitus (GDM) are also listed and are more stringent. It is likely that these goals will change over time. All patients with DM need nutritional counseling, exercise, and self-monitoring of blood glucose. In the past, diabetics were told that they were not allowed to eat Table 5.1  Treatment goals in nonpregnant DM and gestational DM Treatment goals in nonpregnant DM HbA1c Preprandial plasma glucose Peak plasma glucose Blood pressure Low-density lipoprotein High-density lipoprotein Triglycerides Treatment goals in gestational DM Preprandial and either 1 h postmeal 2 h postmeal