What type of diabetes has a gradual onset, usually seen in adults over 40 years of age?

Definition

•

Diabetes mellitus (DM) refers to a syndrome of hyperglycemia resulting from many different causes (see“Etiology”). It is broadly classified into type 1 (T1DM) and type 2 DM (T2DM). The termsinsulin-dependent andnon–insulin-dependent diabetes are obsolete because when a person with type 2 diabetes needs insulin, he or she remains labeled as type 2 and is not reclassified as type 1. Immune-mediated type 1 DM (type 1A) represents 5% to 10% of newly diagnosed diabetics.Tables 1 and2 provide a general comparison of the two types of DM. One difference is that type 1 has usually complete or near-total knockout of insulin reserves mediated solely by immunogenic responses from carriers of certain genotypes, whereas type 2 is of polygenetic origin and may have patients who may start with hyperinsulinemia but have insulin resistance and through environmental factors such as diet and sedentary lifestyle leads to an imbalance between glucagon and insulin levels, resulting in combination of causes toward hyperglycemia.

Some type 1 diabetics also may exhibit high levels of glucagon and not all type 1 diabetics have complete islet cell destruction.

The classification of diabetes also includes:

LADA: Latent autoimmune diabetes of adult onset (sometimes called type 1.5 DM). These individuals are typically not insulin dependent initially and are often misclassified as having type 2 DM.

MODY: Maturity onset diabetes of youth. These have various genetic expressions and can be classified into various subtypes:

MODY 1, 2, 3, 4, and 5 (with 3 being most prevalent: 70% incidence with HNF-1-alpha [12q24] genetic expression)

MODY 7 and 8 (rare)

Ketosis-prone diabetes: Relapsing/remitting beta cell function with slow deterioration over time. It presents with ketoacidosis requiring insulin, then regains beta cell function and patient is able to discontinue insulin. This form is most common under age 40, in those of African or Afro-Caribbean origin, and in obese or overweight patients.

Secondary diabetes:

Pancreatic disease or resection (e.g., cystic fibrosis)

Chronic excessive corticosteroid exposure or Cushing syndrome

Glucagonoma

Acromegaly

Other rare genetic disorders (e.g., mitochondrial diabetes MELAS syndrome)

Rare autoimmune (e.g., type A and B insulin resistance syndrome)

A classification of diabetes mellitus is shown inBox 1

Diabetes mellitus can be diagnosed by the following tests:

A hemoglobin A1c (HbA1c) value ≥6.5% is considered diagnostic for diabetes. This test is preferred because of ease of administration and reliability.

A fasting plasma glucose (FPG) ≥126 mg/dl, which should be confirmed with repeat testing on a different day. Fasting is defined as no caloric intake for at least 8 hr.

An oral glucose tolerance test (OGTT) with a plasma glucose ≥200 mg/dl 2 hr after a 75 g (100 g for pregnant women) glucose load.

Symptoms of hyperglycemia and a casual (random) plasma glucose ≥200 mg/dl are also indicative of DM. Classic symptoms of hyperglycemia include polyuria, polydipsia, and unexplained weight loss. At the time of diagnosis as a diabetic, B-cell function is at 25% to 30%.

Individuals with glucose levels higher than normal but not high enough to meet the criteria for diagnosis of DM are considered to have “prediabetes,” the diagnosis of which is made as follows:

A fasting plasma glucose 100 to 125 mg/dl; this is referred to asimpaired fasting glucose.

After OGTT, a 2-hr plasma glucose of 140 to 199; this is referred to asimpaired glucose tolerance. Patients with impaired glucose tolerance or prediabetes have B-cell function at 50% of normal.

A hemoglobin A1c value of 5.7% to 6.4%.

Table 3 describes diagnostic categories for DM and at-risk states.

Abstract

Diabetes mellitus, especially type 2 diabetes, is an epidemic requiring global attention as a cardiovascular disease (CVD) risk. In addition to well-known microvascular complications such as retinopathy or nephropathy, diabetes confers the substantial burden of CVD morbidity and mortality through macrovascular complications even in early- or pre-stages. Because of its asymptomatic onset and progression, population-based screening is essential for early detection of diabetes mellitus before the development of vascular complications, including CVD. Many modifiable risk factors such as hyperglycemia, hypertension, or dyslipidemia must be adequately and simultaneously controlled for prevention of CVDs in people with established diabetes mellitus.

Cystic Fibrosis–Related Diabetes

SeeChapter 432.

As patients with cystic fibrosis (CF) live longer, an increasing number are being diagnosed withcystic fibrosis–related diabetes (CFRD). Females appear to have a somewhat higher risk of CFRD than males and prevalence increases with increasing age until age 40 yr (there is a decline in prevalence after that, presumably because only the healthiest CF patients survive beyond that age). There is an association with pancreatic insufficiency and there may be a higher risk in patients with class I and class II CF transmembrane conductance regulator mutations. A large multicenter study in the United States reported prevalence (in all ages) of 17% in females and 12% in males. Cross-sectional studies indicate that the prevalence of IGT may be significantly higher than this and up to 65% of children with CF have diminished 1st phase insulin secretion, even when they have normal glucose tolerance. In Denmark, oral glucose tolerance screening of the entire CF population demonstrated no diabetes in patients younger than 10 yr, diabetes in 12% of patients age 10-19 yr, and diabetes in 48% of adults age 20 yr and older. At a Midwestern center where routine annual oral glucose tolerance screening is performed, only about half of children and a quarter of adults were found to have normal glucose tolerance.

Patients with CFRD have features of both T1DM and T2DM. In the pancreas, exocrine tissue is replaced by fibrosis and fat and many of the pancreatic islets are destroyed. The remaining islets demonstrate diminished numbers of β-, α-, and pancreatic polypeptide-secreting cells. Secretion of the islet hormones insulin, glucagon, and pancreatic polypeptide is impaired in patients with CF in response to a variety of secretagogues. This pancreatic damage leads to slowly progressive insulin deficiency, of which the earliest manifestation is an impaired 1st phase insulin response. As patients age, this response becomes progressively delayed and less robust than normal. At the same time, these patients develop insulin resistance due to chronic inflammation and the intermittent use of corticosteroids. Insulin deficiency and insulin resistance lead to a very gradual onset of IGT that eventually evolves into diabetes. In some cases, diabetes may wax and wane with disease exacerbations and the use of corticosteroids. The clinical presentation is similar to that of T2DM in that the onset of the disease is insidious and the occurrence of ketoacidosis is rare. Islet antibody titers are negative. Microvascular complications do develop but may do so at a slower rate than in typical T1DM or T2DM. Macrovascular complications do not appear to be of concern in CFRD, perhaps because of the shortened life span of these patients. Several factors unique to CF influence the onset and the course of diabetes. For example: (1) frequent infections are associated with waxing and waning of insulin resistance; (2) energy needs are increased because of infection and pulmonary disease; (3) malabsorption is common, despite enzyme supplementation; (4) nutrient absorption is altered by abnormal intestinal transit time; (5) liver disease is frequently present; (6) anorexia and nausea are common; (7) there is a wide variation in daily food intake based on the patient's acute health status; and (8) both insulin and glucagon secretion are impaired (in contrast to autoimmune diabetes, in which only insulin secretion is affected).

I Accelerated Atherothrombosis: Epidemiological and Clinical Findings

Diabetes mellitus (DM) is a strong predictor of cardiovascular morbidity and mortality and is associated with both micro- and macrovascular complications.1 Cardiovascular disease (CVD) causes up to 70% of all deaths in people with DM. The epidemic of DM will thus be followed by a burden of diabetes-related vascular diseases. The number of DM patients increases with aging of the population, in part because of the increasing prevalence of obesity and sedentary lifestyle. Although the mortality from coronary artery disease (CAD) in patients without DM has declined since the 1990s, the mortality in men with type 2 diabetes (T2DM) has not changed significantly.2 Moreover, DM is an independent risk factor for heart failure. Heart failure is closely related to diabetic cardiomyopathy: changes in the structure and function of the myocardium are not directly linked to CAD or hypertension. Diabetic cardiomyopathy is clinically characterized by an initial increase in left ventricular stiffness and subclinical diastolic dysfunction, gradually compromising left ventricular systolic function with loss of contractile function and progress into overt congestive heart failure. DM accounts for a significant percentage of patients with a diagnosis of heart failure in epidemiologic studies such as the Framingham Study and the UK Prospective Diabetes Study (UKPDS).2 A 1% increase in glycated hemoglobin (HbA1c) correlates to an increment of 8% in heart failure.3 The prevalence of heart failure in elderly diabetic patients is up to 30%.3

Accelerated atherosclerosis is the main underlying factor contributing to the high risk of atherothrombotic events in DM patients. CAD, peripheral vascular disease, stroke, and increased intima-media thickness are the main macrovascular complications. Diabetics are 2–4 times more likely to develop stroke than people without DM.2 CVD, particularly CAD, is the leading cause of morbidity and mortality in patients with DM.4 Patients with T2DM have a 2- to 4-fold increase in the risk of CAD, and patients with DM but without previous myocardial infarction (MI) carry the same level of risk for subsequent acute coronary events as nondiabetic patients with previous MI.5 Furthermore, people with diabetes have a poorer long-term prognosis after MI, including an increased risk for congestive heart failure and death.

DM is a strong independent predictor of short- and long-term recurrent ischemic events, including mortality, in acute coronary syndrome (ACS),6,7 including unstable angina and non-ST-elevation MI (NSTEMI),8 ST-elevation MI (STEMI) treated medically,9 and ACS undergoing percutaneous coronary intervention (PCI).10,11 Furthermore, the concomitant presence of cardiovascular risk factors and comorbidities that negatively affect the outcomes of ACS is higher in DM patients.12

Heart Failure

The diagnosis and management of HF generally are the same for patients with and without diabetes.Table 51G.4 summarizes diabetes-specific recommendations from the most recent updates of the ACCF/AHA and ESC guidelines for the diagnosis and management of HF in adults.10,11 The staging system for HF identifies diabetes alone as HF stage A,9 reflecting the high risk associated with diabetes for the development of HF, with modest incremental risk in men but threefold increased risk in women for developing HF in the setting of diabetes.

Approximately one third of patients with HF have diabetes. The importance of BP control, preferentially with ACE inhibitors or ARBs, is underscored for the prevention of HF in patients with diabetes. Metformin may be used in patients with stable HF with preserved renal function but should be avoided in patients with unstable HF or that necessitating hospitalization.12 Pioglitazone should not be initiated in patients with NYHA Class III or IV HF, with caution for use in patients with any degree of HF.12 Based on CV outcomes trial results with empagliflozin, the European Society of Cardiology HF Guidelines specifically endorse consideration for the use of empagliflozin for patients with type 2 DM for the prevention of HF.11

Introduction

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. It is among the most common of chronic disorders, affecting up to 5–10% of the adult population of the Western world. The prevalence of diabetes is increasing dramatically; it has been estimated that the worldwide prevalence will increase by more than 50% between the years 2000 and 2030 (Wild et al., 2004). It is clearly established that diabetes mellitus is not a single disease, but a genetically heterogeneous group of disorders that share glucose intolerance in common. The concept of genetic heterogeneity (i.e. that different genetic and/or environmental etiologic factors can result in similar phenotypes) has significantly altered the genetic analysis of this common disorder.

Introduction

Diabetes mellitus is best defined as a syndrome characterized by inappropriate fasting or postprandial hyperglycemia, and its metabolic consequences which include disturbed metabolism of protein and fat. This syndrome results from a deficiency of insulin secretion or its action. Diabetes mellitus occurs when the normal constant of the product of insulin secretion times insulin sensitivity, a parabolic function (Figure 10-1), is inadequate to prevent hyperglycemia and its clinical consequences of polyuria, polydipsia, and weight loss.

By simultaneously considering insulin secretion and insulin action in any given individual, it becomes possible to account for the natural history of diabetes in that person (e.g., remission in a patient with T1 diabetes or ketoacidosis in a person with T2DM). Thus, diabetes mellitus may be the result of absolute insulin deficiency, or of absolute insulin resistance, or a combination of milder defects in both insulin secretion and insulin action.1 Collectively, the syndromes of diabetes mellitus are the most common endocrine/metabolic disorders of childhood and adolescence. The application of molecular biologic tools continues to provide remarkable insights into the etiology, pathophysiology, and genetics of the various forms of diabetes mellitus that result from deficient secretion of insulin or its action at the cellular level.

Morbidity and mortality stem from metabolic derangements and from the long-term complications that affect small and large vessels, resulting in retinopathy, nephropathy, neuropathy, ischemic heart disease, and arterial obstruction with gangrene of extremities.2 The acute clinical manifestations can be fully understood in the context of current knowledge of the secretion and action of insulin.3 Genetic and other etiologic considerations implicate autoimmune mechanisms in the evolution of the most common form of childhood diabetes, known as type 1 diabetes.4,5 Genetic defects in insulin secretion are increasingly recognized and understood as defining the causes of monogenic forms of diabetes such as maturity-onset diabetes of youth (MODY) and neonatal DM and contributing to the spectrum of T2DM.6

There is evidence that the long-term complications are related to the degree and duration of metabolic disturbances.2 These considerations form the basis of standard and innovative therapeutic approaches to this disease that include newer pharmacologic formulations of insulin, delivery by traditional and more physiologic means, and evolving methods to monitor blood glucose to maintain it within desired limits.

Introduction

Diabetes mellitus is the most common metabolic disease in humans and is rising in prevalence in many places in the world, including China, where it has recently been reported as affecting 9.7% of the population. Neurological abnormalities in diabetic patients are common and involve both the central and peripheral nervous system. Type 1, insulin-dependent, or juvenile-onset diabetes mellitus is characterized by onset in childhood or early adolescence, severe hyperglycemia requiring insulin therapy for survival, and susceptibility to diabetic ketoacidosis. This type of diabetes has a prevalence of 1.2–1.9 per 1000 children (younger than 17 years old) and arises from an autoimmune destruction of pancreatic β cells that produce insulin. Type 2, noninsulin-dependent, or adult-onset diabetes mellitus is associated with obesity, sedentary lifestyle, a family history of the disease, and increasing age. It may be controlled by dietary therapy or oral hypoglycemic agents. This form of diabetes has a variable prevalence rate ranging from 5 per 1000 in rural female black Cameroonian Africans to 511 per 1000 in Pima Native Americans, with North American populations ranging from 42 to 78 per 1000. Its cause is likely multifactorial, and it is frequently associated with high circulating insulin levels and tissue resistance to the action of insulin. It may sometimes go unrecognized for months or years and may only be diagnosed in patients when they are hospitalized for other reasons.

Diabetes mellitus is diagnosed by the demonstration of a fasting glucose level of ≥7.0 mmol/liter (126 mg/dl) or a 2-h plasma glucose level of ≥11.1 mmol/liter (200 mg/dl) following a 75-g glucose load. Neurological complications of diabetes mellitus include both acute conditions and chronic disorders arising in association with diabetes. Impaired fasting glucose, or impaired glucose tolerance, conditions that do not fulfill the criteria for frank diabetes mellitus, may also be associated with neurological complications.

Introduction

Diabetes mellitus (DM) is best defined as a syndrome characterized by inappropriate fasting or postprandial hyperglycemia, caused by absolute or relative insulin deficiency and its metabolic consequences, which include disturbed metabolism of protein and fat. This syndrome results from a combination of deficiency of insulin secretion and its action. Diabetes mellitus occurs when the normal constant of the product of insulin secretion times insulin sensitivity, a parabolic function termed the “disposition index” (Figure 19-1), is inadequate to prevent hyperglycemia and its clinical consequences of polyuria, polydipsia, and weight loss. At high degrees of insulin sensitivity, small declines in the ability to secrete insulin cause only mild, clinically imperceptible defects in glucose metabolism. However, irrespective of insulin sensitivity, a minimum amount of insulin is necessary for normal metabolism. Thus, near absolute deficiency of insulin must result in severe metabolic disturbance as occurs in type 1 diabetes mellitus (T1DM). By contrast, with decreasing sensitivity to its action, higher amounts of insulin secretion are required for a normal disposition index. At a critical point in the disposition index curve (see Figure 19-1), a further small decrement in insulin sensitivity requires a large increase in insulin secretion; those who can mount these higher rates of insulin secretion retain normal glucose metabolism, whereas those who cannot increase their insulin secretion because of genetic or acquired defects now manifest clinical diabetes as occurs in type 2 diabetes (T2DM).

By simultaneously considering insulin secretion and insulin action in any given individual, it becomes possible to account for the natural history of diabetes in that person (e.g., remission in a patient with T1 diabetes or ketoacidosis in a person with T2DM). Thus, diabetes mellitus may be the result of absolute insulin deficiency, or of absolute insulin resistance, or a combination of milder defects in both insulin secretion and insulin action.1 Collectively, the syndromes of diabetes mellitus are the most common endocrine/metabolic disorders of childhood and adolescence. The application of molecular biologic tools continues to provide remarkable insights into the etiology, pathophysiology, and genetics of the various forms of diabetes mellitus that result from deficient secretion of insulin or its action at the cellular level.

Morbidity and mortality stem from the metabolic derangements and from the long-term complications that affect small and large vessels, resulting in retinopathy, nephropathy, neuropathy, ischemic heart disease, and arterial obstruction with gangrene of extremities.2 The acute clinical manifestations can be fully understood in the context of current knowledge of the secretion and action of insulin.3 Genetic and other etiologic considerations implicate autoimmune mechanisms in the evolution of the most common form of childhood diabetes, known as type 1a diabetes.4,5 Genetic defects in insulin secretion are increasingly recognized and understood as defining the causes of monogenic forms of diabetes such as maturity-onset diabetes of youth (MODY) and neonatal DM and contributing to the spectrum of T2DM.6

There is strong evidence that the long-term complications are related to the degree and duration of metabolic disturbances.2 These considerations form the basis of standard and innovative therapeutic approaches to this disease that include newer pharmacologic formulations of insulin, delivery by traditional and more physiologic means, and evolving methods to continuously monitor blood glucose to maintain it within desired limits by linking these features to algorithm-driven insulin delivery pumps for an “artificial pancreas.”

86.1 Introduction

Diabetes mellitus is a diagnostic term for a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood sugar. There is variability in its manifestations, wherein some individuals have only asymptomatic glucose intolerance, while others present acutely with diabetic ketoacidosis, and still others develop chronic complications such as nephropathy, neuropathy, retinopathy, or accelerated atherosclerosis. It is among the most common of chronic disorders, affecting up to 5–10% of the adult population of the Western world. Its prevalence varies over the globe, with certain populations, including some American Indian tribes and the inhabitants of Micronesia and Polynesia, having extremely high rates of diabetes (1,2). The prevalence of diabetes is increasing dramatically and it has been estimated that the worldwide prevalence will increase by more than 50% between the years 2000 and 2030 (3).

It is clearly established that diabetes mellitus is not a single disease but a genetically heterogeneous group of disorders that share glucose intolerance in common (4–7). The concept of genetic heterogeneity (i.e. that different genetic and/or environmental etiologic factors can result in similar phenotypes) has significantly altered the genetic analysis of this common disorder. Diabetes and glucose intolerance are not diagnostic terms, but, like anemia, simply describe symptoms and/or laboratory abnormalities that can have a number of distinct etiologies.