Diabetes Mellitus: Impact on Bone, Dental and Musculoskeletal Health

Diabetes Mellitus: Impact on Bone, Dental and Musculoskeletal Health focuses on the under recognized and managed conditions associated with diabetes, including impacts on bone health, dental health, hand, and foot disorders, wounds, infections, and musculoskeletal disorders. A full understanding of the relationship of diabetes to skeletal disorders remains elusive and many physicians who deal with such issues are unclear about causes and management. While the macro- and microvascular complications associated with diabetes mellitus are well known, complications associated with bone, dental and musculoskeletal health are not.

Endocrinologists, primary care physicians, geriatricians, podiatrists, dentists, and researchers interested in diabetes mellitus associated bone, dental and musculoskeletal disorders will find this to be a comprehensive tome on the topic.

• Covers clinically important complications of diabetes that are less understood
• Presents up-to-date, thoroughly referenced information for both clinicians, researchers and other healthcare providers
• Highlights current research and treatment for skeletal deficits and complications due to diabetes types 1 and 2
• Serves as a one-stop resource for the bone, dental and muscular disorders associated with diabetes mellitus

• Language: English
• Publisher: Academic Press
• Release date: Jul 28, 2020
• ISBN: 9780128206201

Book preview

understanding.

Introduction

The hallmark of diabetes mellitus is hyperglycemia. When hyperglycemia is severe, diabetes manifests with polydipsia and polyuria. When it is mild, patients are asymptomatic. Hyperglycemia and its advanced glycation end-products is associated with increased oxidative stress, impaired immune response, and enhanced inflammation. All play a role in the pathogenesis of diabetes complications.

Diabetes affects multiple body systems and may manifest clinically with symptoms and signs of its classic well-known microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral artery disease) complications. Diabetes may also manifest clinically with symptoms and signs of its less-well known complications that affect the bone, dental, musculoskeletal systems.

This book begins with an overview of diabetes and its many complications, accounting for its myriad of clinical presentations. The epidemiology, diagnosis, pathogenesis, management (lifestyle therapy and pharmacotherapy) of the disease and its many complications are covered. This is followed by 3 sections—the first, comprising of 5 chapters, addresses how diabetes impacts bone health; the second, comprising of 2 chapters, describes how diabetes impacts dental health; and the third, comprising of 6 chapters, elucidates how diabetes impacts musculoskeletal health, all in patients who are too sweet.

How diabetes can impact bone health is covered in Chapters 2–6. Chapter 2 provides details on the epidemiology and treatment of How being too sweet leads to skeletal fragility. Osteoporosis and increased fracture risk in both type 1 and type 2 diabetes patients are discussed. Chapter 3 elucidates the cellular and molecular mechanisms of skeletal fragility in diabetes. Chapter 4 presents the preclinical and clinical evidence on how glucose-lowering medications can affect fracture risk in patients with diabetes. The many complex interactions of diabetes, chronic kidney disease, and metabolic bone disease are explained in Chapter 5. Finally, Chapter 6 discusses foot ulcers, osteomyelitis as well as impaired fracture healing in patients with diabetes.

How diabetes can impact dental health is reviewed in Chapters 7 and 8. Chapter 7 elucidates the bidirectional relationships between diabetes and periodontal diseases (gingivitis and periodontitis). Chapter 8 details the association of diabetes with osteomyelitis and osteonecrosis of the jaw.

How diabetes can impact musculoskeletal health are presented in Chapters 9–15. In Chapter 9, the bidirectional relationship between diabetes and sarcopenia (two sides of the same coin) is detailed. Chapter 10 covers the common hand disorders in diabetes—carpal tunnel syndrome, Dupuytren disease, cheiroarthropathy (limited joint mobility) and flexor tenosynovitis (trigger finger). Shoulder disorders [adhesive capsulitis (frozen shoulder) and rotator cuff tendinopathy)] and spine disorders (diffuse idiopathic skeletal hyperostosis and ossification of the posterior longitudinal ligament) together with diabetic amyotrophy, a rare neuropathic disorder resulting in amyotrophy, are discussed in Chapter 11. Charcot foot, a neuropathic arthropathy, is detailed in Chapter 12. Myonecrosis related to diabetes is elucidated in Chapter 13. The association between diabetes with osteoarthritis and gout are discussed in Chapters 14 and 15, respectively.

All these complications add not only a burden to patients with diabetes but also to society at large. Read on to learn and let learn.

Chapter 1: Diabetes mellitus and its many complications

S. Sethu K. Reddya; MengHee Tanb    a Discipline of Medicine, CMU College of Medicine, Mt. Pleasant, MI, United States

b Department of Internal Medicine, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Ann Arbor, MI, United States

Abstract

Diabetes mellitus is a chronic endocrine/metabolic disease with heterogeneous etiologies (mainly via insulin deficiency and/or insulin resistance) and varied clinical presentations. He who knows syphilis knows medicine said Sir William Osler, over a century ago. In 2020, we can say the same about diabetes and its many complications, including the well-known classic microvascular (retinopathy, nephropathy, and neuropathy), and macrovascular (coronary artery disease, cerebrovascular disease, peripheral arterial disease) complications. There are lesser known complications involving bone (osteoporosis, increased fracture risk, impaired fracture healing, and increased bone infections), dental (periodontal disease, gingivitis, and possibly osteonecrosis), and musculoskeletal (sarcopenia, cheiroarthropathy, diabetic myonecrosis, trigger finger, frozen shoulder, rotator cuff tendinopathy, Charcot arthropathy, diffuse idiopathic skeletal hyperostosis, and others) systems. All diabetes complications add a burden to the affected individual and to society. Both the direct and indirect costs (healthcare and related loss of productivity), impact families, friends, and public health programs.

Keywords

Diabetes mellitus; Microvascular; Macrovascular; Bone; Dental; Musculoskeletal complications

Introduction

The International Diabetes Federation estimated there were 352 million people between 20 and 64 years of age with diabetes mellitus (henceforth diabetes) in 2019 globally [1]. This is projected to increase to 417 million people by 2030 and 486 million by 2045. For people between 65 and 99 years of age, there were 111 million in 2019, projected to increase to 195 million by 2030 and 276 million by 2045 million.

Diabetes is a chronic endocrine/metabolic disease with heterogeneous etiologies, clinical presentations and associated complications. Its biochemical hallmark is hyperglycemia (Table 1) [2] caused mainly by insulin deficiency and/or insulin resistance. When hyperglycemia is severe, the classic clinical symptoms are polydipsia and polyuria and, if extreme, diabetes can present with coma. When hyperglycemia is mild, patients with diabetes are asymptomatic, labeling the disease as a silent killer.

Table 1

If the patient has classic symptoms of hyperglycemia, a random PG of ≥   200 mg/dL (11.1 mmol/L) can be diagnostic of diabetes. OGTT, oral glucose tolerance test.

a When unequivocal hyperglycemia is absent, diagnosis requires 2 abnormal results from the same sample or in 2 separate test samples.

Diabetes has many complications [3]—the classic ones are the microvascular (retinopathy, nephropathy, and neuropathy), and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) complications. Diabetes' comorbidities include dyslipidemias, hypertension and obesity. Diabetes also has less well-known complications that impact bone, dental, musculoskeletal health. This chapter briefly reviews the classification, pathogenesis and treatment of diabetes and its classic complications. Additionally, it reviews the bone, dental and musculoskeletal complications that impact the health of patients with diabetes, the theme of this book.

Classification of diabetes

Diabetes is currently classified as follows [2]:

Type 1 diabetes: The hyperglycemia is due to almost absolute insulin deficiency caused by autoimmune destruction of pancreatic β-cells. When islet-cell autoantibodies are absent, type 1 diabetes is considered idiopathic.

Type 2 diabetes: The hyperglycemia is due to insulin resistance together with progressive relative deficiency of insulin.

Gestational diabetes: Hyperglycemia (not present before gestation) diagnostic of diabetes detected for the first time in the 2nd or 3rd trimester of pregnancy.

Other specific types of diabetes: Due to drugs (e.g., glucocorticoids and immune checkpoint inhibitors), monogenic diabetes syndromes (e.g., maturity onset diabetes of the young and neonatal diabetes), after organ transplantation, diseases of exocrine pancreas (e.g., cystic fibrosis and pancreatitis) and others.

Pathogenesis of type 1 diabetes

Type 1 diabetes occurs as a result of chronic autoimmune destruction of the pancreatic β-cells, leading to almost absolute insulin deficiency [4]. It often occurs in children and young adults but can present at any age, even in senior citizens. The highest prevalence is in Europe, but the incidence has been growing in regions like India, Middle East and sub-Saharan Africa. Clinically, the presentation may be dramatic with severe hyperglycemia and associated dehydration, acidosis and even coma. However, behind the scenes, the autoimmune destruction may have been occurring for 10 years or more. An individual may be able to regulate one's blood glucose with 10–20% of pancreatic function. In addition to controlling one's blood glucose with insulin therapy, the research challenges include whether we can prevent type 1 diabetes, reverse early type 1 diabetes and prevent long-term complications.

The current hypothesis is that in a genetically susceptible individual, one's immune system launches a cell-mediated immune attack on the β-cells and this damage leads to β-cell proteins exposed to the immune system, including the antibody producing cells. These islet autoantibodies (IAA) can be detected in the serum, particularly in the early years of the diabetes [5]. The genetic traits that carry higher risk typically are related to how the body recognizes self from non-self (e.g., histocompatibility traits that are important in organ transplantation).

At disease onset IAA is found in 35–60% of young children but their frequency is less in teenagers and adults. By itself, IAA is not highly predictive but can be used in combination with other islet autoantibodies for prediction. Autoantibodies to glutamic acid decarboxylase (GAD) have been proven to be valuable markers for type 1 diabetes and are detectable many years before the clinical onset of the disease and are seen in both Islet Cell Antibody (ICA) positive and ICA-negative First-Degree Relatives (FDR) subjects. Approximately 70–80% of newly diagnosed type 1 diabetes patients and 3–5% of FDR have autoantibody to GAD. IA-2A and IA-2B autoantibodies are detected in more than 55–75% of newly diagnosed type 1 diabetes patients. These autoantibodies normally appear after insulin auto-antibodies and/or GAD antibodies. The zinc transporter autoantibodies (ZnT8A) were detected in 60–80% of new-onset type 1 diabetes compared with <   2% of controls and <   3% type 2 diabetes patients and in up to 30% of patients with other autoimmune disorders with a type 1 diabetes association.

The risk of developing diabetes is strongly correlated to the number of autoantibody markers, that is, the presence of two or more autoantibodies gives a higher probability of developing the disease than the presence of single antibody. The anti-insulin antibody is usually the earliest biomarker of autoimmunity.

Autoantibodies usefulness may be limited. First, the appearance of autoantibodies marks a relatively late stage of the autoimmune process and, therefore, is not suitable for early disease intervention. Second, only a subset of the autoantibody-positive subjects will progress to clinical diabetes and, therefore, it would be useful to have biomarkers that allow the distinction of the progressors versus non-progressors. Third, autoantibodies are not useful as biomarkers for therapeutic outcomes.

The dilemma in trying to prevent type 1 diabetes is that one would like to intervene early, when there is still significant pancreatic reserve remaining. However, in this very early stage, many may not actually progress to diabetes and thus one would need to unnecessarily treat many people to prevent one case of type 1 diabetes. Thus, more benign therapies have been tested in the very early stages of the autoimmune process, while more toxic and complicated therapies have been used in those in late stages of the autoimmune process or in those who recently developed diabetes.

Strategies to prevent type 1 diabetes have included approaches to inhibit the immune system from damaging the pancreas or approaches to improve the immune tolerance of the pancreas [6].

Pathogenesis of type 2 diabetes

The increase in prevalence of type 2 diabetes is primarily due to increasing incidence of diabetes in the developing world [1]. Preceding the surge in incidence of type 2 diabetes is the increasing incidence of obesity, related to reduced physical activity and increased caloric intake.

What causes the hyperglycemia in type 2 diabetes? Although insulin resistance and relative insulin deficiency play a dominant role, other pathophysiologic mechanisms may also contribute to development of type 2 diabetes [7]. There may be excess glucose production from the liver, decreased glucose uptake in muscle and fat and increased re-absorption of glucose at the kidney level. The brain which can regulate appetite, pancreatic and liver function may also play a role. The α-cells in the pancreas secrete glucagon which typically opposes the effects of insulin and is thus called a counter-regulatory hormone. When one eats food, the L-cells in the gut (ileum and colon) secrete hormones (incretins) which stimulate insulin secretion and suppress glucagon in a post-meal glucose-dependent manner. This phenomenon is thought to be sub-optimal in type 2 diabetes. Finally, visceral obesity (intra-abdominal fat) may also be related to inflammation, lipid storage problems and insulin resistance. There is also strong evidence that fat cells can make their own set of hormones which can impact the liver, pancreas and even the brain.

Lipotoxicity is often increased in insulin resistance states due to higher levels of free fatty acids which impair β-cell function and contribute to β-cell apoptosis and insulin resistance [8, 9]. Muscle cells and hepatocytes are negatively affected by excessive amounts of fatty acids, which cause increased ceramide accumulation, activate inflammatory pathways, and increase the release of reactive oxygen species (ROS) and enhance apoptosis [10].

The role of pro-inflammatory cytokines in the destruction of pancreatic β cells and the development of type 2 diabetes has been validated; potential anti-inflammatory interventions [11] such as blocking IL-1β receptors, or tumor necrosis factor (TNF) or using salsalate to inhibit nuclear factor-κβ pathway have been found to be positive in early studies, but are not ready for prime time use yet.

During the natural history of type 2 diabetes, individuals may progress from normal glucose tolerance to prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and finally to overt diabetes. The key variable in this progression appears to be failing β-cell secretion of insulin. Non-progressors maintain their insulin secretion capacity while the progressors have continued decline in insulin secretion [12]. Both β-cell mass and function appear to be adversely affected in type 2 diabetes.

Bariatric surgery is now used to treat obesity associated type 2 diabetes [13]. The most popular procedure, Roux-en-Y gastric bypass procedure, has been shown to increase ghrelin levels which suppress appetite and increase incretin (particularly GLP-1 (glucagon-like-peptide 1) levels.

As we discover new pathways implicated in development of type 2 diabetes this may lead to new strategies to treat diabetes [14].

Treatment of diabetes

All patients with diabetes are treated with dietary [15] plus exercise therapy [16] and most also require pharmacotherapy using glucose-lowering medications (GLMs) to attain and maintain good glycemic control.

Dietary and exercise therapy (Tables 2 and 3)

Dietary management (Table 2) is the cornerstone of diabetes care [17] and should be used in conjunction with exercise (Table 3) to promote a healthy lifestyle.

Table 2

Table 3

Hopefully, this leads to the maintenance of a lower or ideal body weight, decreased insulin resistance, and improved control of hyperglycemia, dyslipidemia, and hypertension. Individuals with diabetes should be referred to a registered dietitian for detailed, practical advice. Physicians can help greatly by inquiring about a patient's lifestyle and imparting good nutritional principles. Special attention to salt intake, smoking and alcohol intake must be considered. Nutrition advice needs to be personalized to the individual patient.

Exercise (Table 3) is important for overall health and is especially beneficial for helping achieve improved glycemic control in those with type 2 diabetes [18].

Exercise program also needs to be individualized according to the patient's needs and his/her co-morbidities. The incorporation of continuous glucose monitoring should minimize issues with exercise-related glucose fluctuations [19].

Pharmacotherapy for diabetes (Table 4 and Fig. 1)

Almost all people with diabetes need GLMs and diet plus physical activity therapy to achieve good glycemic control. Patients with type 1 diabetes require insulin plus diet and exercise; some may add amylin analog as adjunct therapy. For those with type 2 diabetes, the initial therapy is diet and exercise; if glycemic goal is not achieved, metformin is added (unless contraindicated or cannot be tolerated). If this metformin monotherapy does not reach glycemic goal, a 2nd GLM is added, followed by a 3rd and 4th in a stepwise, sequential approach guided by the comorbidities and the patient's needs [20]. Table 4 summarizes the 13 classes of GLMs and their physiologic effects and mechanisms of actions. Fig. 1 shows an approach to initial combination GLM therapy in managing type 2 diabetes. Guidelines for adding the 3rd and 4th GLM are also available [20].

Table 4

Ca, calcium; DPP-4, dipeptidyl peptidase-4; FFA, free fatty acids; GLP-RA, glucagon-like peptide receptor agonists; TGR5, G-protein-coupled bile acid receptor; IR, insulin receptor; IRS, insulin receptor substrate; KATP, ATP potassium sensitive channels; LPL, lipoprotein lipase; PPAR-γ, peroxisome proliferator-activated receptor gamma; SGLT-2, sodium glucose co-transporte-2; SU, sulfonylureas; TG, triglycerides.

Fig. 1 Approach to initiating combination glucose-lowering medications therapy in type 2 diabetes mellitus.

ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CVOTs, cardiovascular outcomes trials; DPP-4i, dipeptidyl peptidase-4 inhibitors; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon like peptide-1 receptor agonist; HF, heart failure; SGLT-2i, sodium glucose cotransporter-2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione; wt, weight; ↓, decrease; ↑, increase. Adapted from American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in diabetes-2019. Diabetes Care 2019;42(Suppl. 1):S90–102.

Complications of diabetes

The classic complications of diabetes are its microvascular and macrovascular complications [3]. Other complications less-well known are those that affect the bone, dental, musculoskeletal systems. We shall review these next.

Pathogenesis of microvascular complications of diabetes

The pathogenesis of the microvascular complications of diabetes is complex involving multiple mechanisms. We shall briefly summarize these.

Hyperglycemia and advanced glycation end-products

The chronic hyperglycemia to which patients with diabetes are exposed is paramount in the etiology of diabetic complications. Hyperglycemia may play a role via several mechanisms:

•Non-enzymatic glycosylation of protein structures, leading to altered blood vessel function.

•Conversion of glucose to sorbitol via intracellular aldose reductase enzyme, leading to an accumulation of sorbitol, which, in turn, can have several deleterious effects on cellular function.

•Adverse effects on coagulability, platelet function, atherogenic potential of lipoproteins.

•Increased susceptibility to free oxygen radical-induced damage.

Hyperglycemia is believed to contribute to oxidative stress [21] via the polyol pathway, the hexosamine pathway and activation of protein kinase C. Hyperglycemia also leads to greater activation of the pro-inflammatory transcription factor [22] nuclear factor-kappa B (NF-κB) [23] by protein kinase C in vitro. Hyperglycemia also results in the oxidation of sorbitol by NAD   +, thereby increasing the cytosolic NADH:NAD+ ratio and consequently inhibiting glyceraldehyde-3-phosphate dehydrogenase activation.

Advanced glycation end products (AGEs) are formed by the non-enzymatic reaction of glucose and other glycating compounds that are derived from glucose and increased fatty acid oxidation [24]. Intracellular hyperglycemia is the primary initiating event in the formation of both intracellular and extracellular AGEs. Extracellular matrix components that have been modified by AGE precursors interact abnormally with other matrix proteins and their receptors on cells. Several AGE receptors are linked to increased inflammation, including receptor for AGE (RAGE). Proteins can be structurally modified by glycosylation, thereby affecting their function. Alternatively, AGE binding to RAGE can induce the production of reactive oxygen species, the production of inflammatory cytokines such as tumor necrosis-alpha (TNF-α), and the activation of NF-κB.

Oxidative stress

Hyperglycemia leads to the overproduction of superoxides in mitochondria. This increase in superoxide production activates several pathways including polyol pathway flux, increased AGE formation and RAGE expression, activation of protein kinase C and the hexosamine pathway. Inflammation induced by increased intracellular ROS also contributes to diabetic complications. After ROS deplete cellular antioxidant defenses, ROS not only destroy cells and tissues but also act as intracellular second messengers [25]. Oxidative stress can also induce the activation of multiple serine kinases, which impair the capacity of insulin to stimulate protein kinase B activation and glucose transport. NF-κB, p38 MAPK and the JNK/SAPK pathway are sensitive to oxidative stress, which is linked to impaired insulin action and the development of the late diabetic complications [26].

Immune response

The reduction in circulating neutrophils that is observed in type 1 diabetes might be due to impaired neutrophil differentiation and output from bone marrow, increased neutrophil apoptosis or anti-neutrophil-specific antibodies, and increased recruitment into tissues ) production, defective chemotaxis, and phagocytosis. A study has shown that infiltrating monocytes in type 1 diabetes patients spontaneously secrete pro-inflammatory cytokines, which are known to induce and expand Th17 cells [28]. Evidence also shows that the classically activated macrophages initiate insulitis and β-cell death in type 1 diabetes patients and play a role in insulin resistance in type 2 diabetes by triggering an inflammatory response. In contrast, alternatively activated macrophages exert a protective effect in diabetes by attenuating tissue inflammation [29].

Pro-inflammatory factors

Adipokines may be relevant to the pathogenesis of diabetes and its complications. Crosstalk between adipocytes, macrophages, and immune cells in the expanding adipose tissue make the adipose tissue a major production site of inflammatory markers [30]. Inflammatory mediators might play a dual role in type 2 diabetes, contributing to hyperglycemia-induced insulin resistance and contributing to diabetic complications [31]. Pro-inflammatory factors, such as TNF-α, IL-1β, IL-6 and IL-18, are reportedly increased in diabetes and contribute to insulin resistance by both JNK and the IKKβ/NF-κB pathway [32]. Enhanced production of inflammatory cytokines is thought to contribute not only to insulin resistance and β-cell apoptosis, but also involved in the development of diabetic complications [33].

Microvascular complications [34]

Retinopathy

Diabetes is responsible for 8% of cases of blindness in the United States and is the leading cause of blindness in the 20- to 64-year age range. The most common form of retinopathy is non-proliferative (background) retinopathy consisting of microaneurysms, intra-retinal hemorrhages, or exudates. Infarction of the nerve layer of the retina may occur, causing cotton-wool exudates. This ischemia is thought to play a role in the eventual proliferation of new, friable vessels from the retina into the vitreous. This latter phase, termed proliferative retinopathy, is associated with vitreous hemorrhages, retinal scarring, and potential retinal detachment [35]. An altered expression of various local growth factors within the retina is thought to mediate the vascular changes in the retina. Macular edema is also more prevalent in people with diabetes and may occur with or without proliferative retinopathy. Patients with diabetes should be referred to an ophthalmologist at the time of diagnosis of type 2 diabetes, whereas referral to an ophthalmologist should be made 5 years after the diagnosis of type 1 diabetes if the patient is asymptomatic.

The most important risk factors for retinopathy include:

•Duration of diabetes

•Glycemic control

•Hypertension

Depending on the stage of retinopathy, management includes the following options:

•Appropriately frequent funduscopic examination (more often during pregnancy)

•Improved control of hyperglycemia and hypertension

•Early laser treatment

•Vitrectomy

Aspirin therapy does not appear to have adverse ophthalmic effects.

Nephropathy

Renal failure is a major cause of mortality in people with diabetes. In the United States, approximately one in three patients on dialysis has diabetes. Whereas retinopathy eventually occurs in almost all patients with diabetes, clinical nephropathy develops in about 40% of patients with type 1 diabetes and in less than 20% of those with type 2 diabetes. The most important risk factors for nephropathy include:

•Duration of diabetes

•Glycemic control

•Hypertension

•Smoking

•Dyslipidemias

Recent prospective studies lend support to the hypothesis that smoking accelerates (almost twofold) nephropathy in patients with diabetes [36]. Recent interest has focused on the polymorphism of various genes linked to hypertension, such as the angiotensin-converting enzyme (ACE) gene [37]. Proteinuria, which is 15 times more frequent in patients with diabetes than those without, worsens the prognosis and is a prognostic factor with respect to renal failure and macrovascular disease.

All patients with diabetes, 12 to 70 years of age, should undergo urine testing for urinary albumin/creatinine ratio at least annually [38]. Ideally, individuals should be metabolically stable at the time of testing. Heavy exercise, urinary tract infection, acute febrile illness, or heart failure may transiently increase urinary albumin excretion. Non-steroidal anti-inflammatory drugs and ACE inhibitors should be avoided during screening.

In most circumstances, the blood pressure should be lower than 140/90 mmHg, but in patients with microalbuminuria, it should be 130/85 mmHg or lower [39]. The first measures should be to improve glycemic control, to achieve an optimal body weight and smoking cessation, and to follow the proper lifestyle. Subsequently, ACE inhibitors, calcium channel blockers, and α-blockers may be used. In the presence of microalbuminuria, an ACE inhibitor or angiotensin receptor blocker (ARB) is generally favored. New exciting data has suggested that SGLT2 inhibitors may offer renal protection [40].

Neuropathy

Neuropathy, one of the most common complications of diabetes, can affect the sensory, motor, and autonomic nervous systems [41]. Painful symptoms or paresthesia develop in some people with diabetes. For peripheral painful neuropathy [42], simple analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, gabapentin and pregabalin are commonly used. Other causes of neuropathy should always be ruled out before diabetes is assumed to be the cause.

Hypoglycemic unawareness, a sign of autonomic dysfunction, is often present in patients with type 1 diabetes for more than 15 years. At this point, intensive control of diabetes may be problematic, and appropriately higher targets for blood glucose control should be set. CGM technology should allow safer achievement of improved glucose control in this setting.

Symptoms of postural hypotension are associated with a poor prognosis in people with diabetes. Traditionally, norepinephrine bitartrate, fludrocortisone acetate, or proamatine have been used. Patients may also respond to low doses of a β-blocker. For associated nocturnal diarrhea, once infectious causes have been ruled out, clonidine or a bile acid sequestrant may be helpful [43].

Autonomic dysfunction may affect the gastrointestinal or genitourinary systems, resulting in constipation, gastroparesis, diabetic diarrhea, erectile dysfunction, or a neurogenic bladder.

It is crucial to always consider causes other than diabetes in the etiology of any neuropathy.

Macrovascular complications

Atherosclerotic vascular disease is a major cause of morbidity and mortality in patients with diabetes [44]. For those with type 1 diabetes, more than one third of mortality is due to cardiac and cerebrovascular diseases; for those with type 2 diabetes, two thirds of mortality are the result of macrovascular disease [45].

Age and blood pressure are the strongest risk factors related to subsequent death from coronary heart disease. Cigarette smoking, dyslipidemias, and hyperinsulinemia are also important co-risk factors in diabetes [46]. It is reassuring that interventions for vascular disease, including the new class of PCSK9 inhibitors [47] are equally effective in those with or without diabetes [48].

Bone complications

The risk of fragility fractures is increased in people with diabetes [49]. Compared to controls, bone mineral density (BMD) is decreased in type 1 diabetes, and often normal or even slightly elevated in type 2 diabetes. However, both types of diabetes are associated with decreased bone turnover together with microstructural changes, especially with the presence of microvascular complications. Hyperglycemia, oxidative stress and the accumulation of AGEs have been implicated in altered collagen, increased marrow adiposity, release of inflammatory adipokines, and potentially altered osteocyte function [50]. Other factors to consider include potential harm from hypoglycemia leading to increased risk of falling, and direct bone effect from treatments (e.g., thiazolidinediones). Commonly known complications of diabetes mellitus, such as neuropathy, poor balance, sarcopenia, vision impairment and frequent hypoglycemic events all increase the risk of falls and fractures.

SGLT2-inhibitors also have been associated with changes in calcium/phosphorus homeostasis.

Low bone turnover, accumulation of AGEs, micro- and macro-architecture alterations and tissue material damage lead to abnormal biomechanical properties and weaker bone.

A large case control study in Denmark reported a relative risk for any fracture: odds ratio [OR] = 1.3 (95% CI 1.2–1.5) for type 1 diabetes and OR = 1.2 (95% CI 1.1–1.3) for type 2 diabetes after adjustment for confounders [51]. In a Swedish study the risk factors most associated with low-energy fracture was diabetes in both men relative risk [RR] = 2.38 (95% CI 1.65–3.42) and women [RR] = 1.95 (95% CI 1.33–2.86) [52]. Women with type 2 diabetes have a threefold higher risk of vertebral fracture compared to women who are non-diabetic. In the women's Health Initiative Study, the risk of proximal humerus, foot, and ankle fractures was also found to be higher among women with type 2 diabetes than among healthy controls [53].

Decreased BMD, bone formation, reduced bone quality and diabetic vascular complications are associated with an increased risk of fractures. In type 2 diabetes, even though BMD may be normal or increased, the fracture risk is increased [54], partially due to increased propensity for falls [55].

There is suggestion that patients with diabetes exhibit decreased osteoblast activity [56]. Fracture healing is also delayed in diabetic patients [57]. Human studies of diabetes generally indicate that osteoclasto-genesis is enhanced. Patients with type 2 diabetes exhibit increased circulating levels of tartrate-resistant acid phosphatase, which is indicative of increased osteoclast activity. In patients with type 1 diabetes or type 2 diabetes, poor glycemic control leads to increased bone resorption and bone loss [58].

In this book, how diabetes impacts bone health is reviewed in Chapters 2–6.

Dental complications

Diabetes and periodontitis are chronic non‐communicable diseases independently associated with mortality and have a bidirectional relationship [59].

There is strong evidence that people with periodontitis have elevated risk for dysglycemia and insulin resistance and thus an increased risk of type 2 diabetes. Diabetes may promote periodontitis through an exaggerated inflammatory response to the periodontal microflora [60].

Dietary changes with increased simple sugars and reduced complex carbohydrates and fiber may have consequences for an unhealthy oral microenvironment. The glucose released into the saliva can be metabolized to lactic acid by plaque; this results in decreased salivary pH and increases acidophilic bacteria [61]. Thus, there may be changes in oral microbiome. It is hypothesized that ensuing changes in the dental biofilm can lead to dental decay and periodontal diseases [62].

A cross-sectional study from Atlanta concluded that dental loss is common in those with diabetes and is associated with older age, diabetic retinopathy and not flossing [63].

Gingivitis is also more common in diabetes. Changes in microflora can affect gingival health. Gingiva can also be a good source of mesenchymal stem cells [64]. Gingivitis and periodontal disease appear to be associated with obesity and insulin resistance [65]. Gingivitis may begin in childhood and later lead to periodontal disease.

Gingivitis and periodontitis are inflammatory disorders of the periodontium, often associated with other conditions and complications such as diabetes, atheroma and cardiovascular diseases [66]. The direct pathophysiology is still unclear but postulated to link to infiltration of hyperinflammatory immune cells, bacteremia [67].

One does have to be careful in hidden biases in managing periodontal disease in older adults. Ageism may result in reduced access to quality dental care and in a reduced quality of life. Close attention to dental hygiene and early interventional procedures are key to maintaining oral health [68].

Osteomyelitis and osteonecrosis of the jaw are associated with diabetes.

In this book, the ways diabetes can impact dental health are reviewed in Chapters 7 and 8.

Musculoskeletal complications

Sarcopenia and diabetes

Sarcopenia is characterized by decrease in muscle function (strength and/or physical performance) and mass. The incidence and prevalence sarcopenia and diabetes mellitus increase as people age. A systematic review and meta-analysis of observational studies (involving 54,676 participants with mean age of 65.4 years) reported an association of diabetes and sarcopenia [69]. Patients with diabetes had a higher prevalence of sarcopenia compared with controls: odds ratio (OR) = 1.64 (95% CI 1.20–2.22). Patients with sarcopenia have an increased prevalence of diabetes: OR = 2.07 (95% CI 1.4–3.62). These 2 common chronic diseases have a bidirectional relationship and have been described as two sides on the same coin [70].

Sarcopenia has been associated with many changes in the body during aging including derangements in skeletal muscle metabolism (glucose, protein and lipid), diabetes, changes in hormones (testosterone), chronic inflammation, oxidative stress, mitochondrial dysfunction, impaired blood flow to muscle, physical inactivity and decline in satellite cells performance in muscle [71].

Musculoskeletal disorders in diabetes

Patients with diabetes have a higher prevalence of musculoskeletal disorders compared to the general population. Diabetes affects all components of musculoskeletal system including muscles, bones and connective tissue. The spectrum of musculoskeletal disorders in diabetes is wide involving hand, shoulder, lower limb, and spine [72]. Although most of these musculoskeletal disorders are also seen in people without diabetes, some are specific or related to diabetes, some are more frequently observed in but are not specific to diabetes, and some are likely associated with diabetes.

The musculoskeletal disorders in patients with diabetes have been classified differently by various groups. Combining one according to the type musculoskeletal system component affected [73] with another classification according to the musculoskeletal complication's association with diabetes [74] we present a hybrid classification (Table 5).

Table 5

I, incidence; P, prevalence.

A recent systematic review and meta-analysis of 21 studies reported the prevalence of musculoskeletal disorders in 13,744 subjects with diabetes was 58.15% (95% CI 41.4%–73.9%) [75]. The most common area of the body affected was the hand with a prevalence of 33.05% (95% CI 21.1–46.13) followed by the shoulder with a prevalence of 31.6% (95% CI 13.0–53.8). In a population-based cohort study in Taiwan people with diabetes were 1.32 95% CI 1.25–1.40) times more likely to have carpel tunnel syndrome and 1.51 (95% CI 1.42–1.59) times more likely to have trigger finger [76].

In this book, the many ways diabetes can impact musculoskeletal health are presented in Chapters 9–15.

Conclusion

Diabetes mellitus is a common, growing and costly public health problem. It is of note that some of the pathogenic mechanisms that are thought to cause diabetes are also playing a role in the associated complications, albeit enhanced by the presence of hyperglycemia. Hyperglycemia is the hallmark of diabetes and not surprisingly, in time, almost any exposed organ to hyperglycemia can be damaged. The complications of diabetes include not only the classic well-known microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral artery disease) complications, but also those less-known complications that affect bone (osteoporosis, increased fracture risk, impaired fracture healing, and increased bone infections), dental (periodontal disease, gingivitis as well as osteomyelitis and osteonecrosis of the jaw) and musculo- skeletal (sarcopenia, cheiroarthropathy, Dupuytren disease, carpal tunnel syndrome, stenosing flexor tenosynovitis (trigger finger), frozen shoulder (adhesive capsulitis), rotator cuff tendinopathy, Charcot arthropathy, diabetic myonecrosis, diffuse idiopathic skeletal hyperostosis, diabetic amyotrophy, osteoarthritis and gout) systems. Diabetes also has skin