What is the reason for the symptoms of polyuria polydipsia and polyphagia in type 1 diabetes mellitus?

Diagnosis

A diagnosis of diabetes has historically included an elevated fasting blood glucose level, any glucose value higher than 200 mg/dL (11 mmol/L) with symptoms of hyperglycemia, or an abnormal 2-hour oral glucose tolerance test (OGTT).9 American Diabetes Association (ADA) guidelines for the diagnosis of diabetes were modified in 2009 to include a hemoglobin A1c (HbA1c) value greater than 6.5%.10 Under certain settings (e.g., obesity, racial status other than Caucasian) and particularly among adults, the diagnosis of T1DM versus type 2 diabetes mellitus (T2DM) can prove quite challenging. At present, the best criterion for separating the two disorders resides in laboratory identification of any one of a number of islet cell autoantibodies (also known as T1DM-associated autoantibodies; i.e., anti-insulin autoantibodies [IAA], anti–glutamic acid decarboxylase [GADA], anti–insulinoma-associated antigen 2 [IA2A], or anti-zinc-transporter 8 [ZnT8A]). Literally hundreds of studies over the past three decades have suggested that the presence of these autoantibodies provides high sensitivity for diagnosing persons with T1DM.11 Indeed, more than 90% of Caucasian children presenting with diabetes express at least one of these four T1DM-associated autoantibodies.12 In terms of disease specificity, T1DM-associated autoantibodies are typically positive in less than 1% to 2% of unaffected (i.e., non-T1DM) individuals, further validating their diagnostic utility. However, among African-American and Latino children and adolescents in the United States diagnosed with diabetes, almost one half lack any T1DM-associated autoantibody. Many patients from these ethnic minorities in the United States present clinically as if they have early-onset T2DM (e.g., mild ketosis, slow symptomatic onset), some have attendant risk factors such as obesity, and many lack human leukocyte antigen (HLA) alleles associated with T1DM. Increasingly diverse genetic admixtures, due to geographic migration and social changes (e.g., multiracial offspring), further contribute to diagnostic complexity.

In childhood and adolescence, two peaks of T1DM presentation occur: a smaller peak between 5 and 7 years of age and a larger peak at or near puberty.13 Although most autoimmune disorders disproportionately target females, T1DM affects males slightly more than females. The incidence of T1DM varies with seasonal changes and birth month. Incidence of T1DM diagnosis is higher in autumn and winter, whereas being born in the spring is associated with an increased likelihood for T1DM.14 Interestingly, the development of T1DM-associated autoimmunity (i.e., the formation of islet autoantibodies) in the months to years prior to the onset of symptomatic T1DM also shows a degree of seasonal synchronization.

The measurement and presence of T1DM-associated autoantibodies have also fueled much debate regarding the percentage of T1DM cases that are errantly misclassified as T2DM. Indeed, it is conceivable that 5% to 15% of adults diagnosed with T2DM may have T1DM, given the frequency of T1DM-associated autoantibodies in populations diagnosed with T2DM.15 This is, in effect, a problem in health care provider recognition of the potential for T1DM disease in adult populations combined with a lack of widespread screening for such autoantibodies in settings in which screening would seem warranted. If this assertion is correct, given the vastly greater number of persons diagnosed with T2DM (relative to that of T1DM), the number of actual T1DM cases in a given population may be massively underestimated. This is therapeutically unfortunate because an accurate diagnosis of T1DM is vital; persons misdiagnosed as having T2DM when they indeed have T1DM experience higher HbA1c, have risk of diabetic ketoacidosis (DKA) due to use of noninsulin therapies, and have accelerated progression toward micro- and macrovascular complications..

Adverse effects

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Clinical signs of bromide toxicity appear to be dose dependent and include polyphagia, vomiting, anorexia, constipation, pruritus, muscle pain, sedation and pelvic limb weakness.

Asthma (may be fatal) is associated with bromide administration in cats.

Ataxia and sedation are the major dose-limiting adverse effects in dogs.

Other infrequently reported adverse effects in dogs include pancreatitis, increased attention seeking, aggression, coprophagia and hyperactivity.

High-dose bromide therapy has been associated with thyroid dysfunction in humans and rats.

Bromide toxicity was reported in a dog with renal insufficiency, resulting in decreased clearance of bromide and therefore a higher serum bromide concentration.

Reduced seizure control was reported in a dog fed a high-chloride diet. Toxic concentrations of bromide may be reached rapidly when chloride intake is decreased.

Bromide readily crosses the placenta in humans and may cause neonatal bromism. Because of the lack of information in dogs, bromide should be avoided in breeding animals.

Sodium bromide should not be used in dogs with congestive heart failure, hypertension or liver failure.

Potassium bromide should be used cautiously in dogs with hypoadrenocorticism.

Type 2 Diabetes and Gestational Diabetes

The pathophysiology of type 2 diabetes involves abnormalities of both insulin-sensitive tissue (i.e., both a decrease in skeletal muscle and hepatic sensitivity to insulin) and β-cell response as manifested by inadequate insulin release for a given degree of glycemia. Initially, in the course of the development of type 2 diabetes, the insulin response to a glucose challenge may be increased relative to that of individuals with normal glucose tolerance, but it is inadequate to maintain normoglycemia. Whether decreased insulin sensitivity precedes β-cell dysfunction in the development of type 2 diabetes continues to be debated. Arguments and experimental data support both hypotheses.

Despite the limitations of any classification system, certain generalizations can be made regarding women with type 2 diabetes or GDM. These individuals are typically older and more often have higher BMI compared with individuals with normal glucose tolerance. The onset of the disorder is usually insidious, with few patients complaining of the classic triad of symptoms seen at the onset of type 1 diabetes—polydipsia, polyphagia, and polyuria. Individuals with type 2 diabetes are often initially told to lose weight, increase their activity (i.e., exercise), and follow a diet low in saturated fats and high in complex carbohydrates. Oral agents are frequently used to increase insulin response, enhance insulin sensitivity, or increase renal excretion of glucose. Individuals with type 2 diabetes may eventually require insulin therapy to maintain euglycemia but are at significantly less risk for DKA.Data from monozygotic twin studies have reported a lifetime risk for both twins developing type 2 diabetes that ranges between 58% and almost 100%, suggesting that the disorder has a strong genetic component.

Type 2 pregestational diabetes is usually classified as class B diabetes according to the White classification system. Women who develop GDM—glucose intolerance first diagnosed in the second or third trimester of pregnancy that is not clearly either preexisting type 1 or type 2 diabetes—share many of the metabolic characteristics of women with type 2 diabetes. Although earlier studies reported a 10% to 35% incidence of islet cell antibodies in women with GDM as measured by immunofluorescence techniques, research using specific monoclonal antibodies has described a much lower incidence, on the order of 1% to 2%, suggesting a low risk for type 1 diabetes in women with GDM. Furthermore, postpartum studies of women with GDM have demonstrated defects in insulin secretory response and decreased insulin sensitivity, indicating that the typical abnormalities in glucose metabolism seen in type 2 diabetes are present in women with GDM and may well have existed prior to pregnancy complicated by GDM. The alterations in insulin secretory response and insulin resistance in women with a previous history of GDM compared with a weight-matched control group may differ depending on whether the women with previous GDM are lean or obese.15 Thus, in women with GDM, the hormonal events of pregnancy may unmask a genetic susceptibility to type 2 diabetes.

CLINICAL MANIFESTATIONS OF DIABETES MELLITUS

The classic presentation of diabetes in children is a history of polyuria, polydipsia, polyphagia, and weight loss. Polyuria may be heralded by the recurrence of bedwetting in a previously toilet trained child and polydipsia by a child constantly requesting fluids to drink. Unexplained weight loss should raise suspicion of the existence of diabetes that should be confirmed or excluded by measurement of blood glucose concentration first in the postprandial and later in the fasting state. The urine should also be checked for the presence of glucosuria. The duration of these symptoms varies but is often less than 1 month.

An insidious onset with lethargy, weakness, and weight loss is also quite common. The loss of weight despite increased dietary intake is readily explicable by the following example. The average healthy 10-year-old child has a daily caloric intake of 2,000 or more calories, of which approximately 50% are derived from carbohydrates. With the development of diabetes, daily losses of water and glucose may be as much as 5 L and 250 g, respectively. This represents 1,000 calories lost in the urine, or 50% of average daily caloric intake. Therefore, despite the child's compensatory increased intake of food and water the calories cannot be utilized, excessive caloric losses continue, and increasing catabolism and weight loss ensue.

Pyogenic skin infections and candidal vaginitis in girls or candidal balanitis in uncircumsized boys are occasionally present at the time of diagnosis of diabetes. They are rarely the sole clinical manifestations of diabetes in children, and a careful history will invariably reveal the coexistence of polyuria, polydipsia, and perhaps weight loss. Ketoacidosis is responsible for the initial presentation of many (about 25 to 40%) diabetic children. Ketoacidosis is likely to be present more often in children younger than 5 years of age because the diagnosis may not be suspected and a history of polyuria and polydipsia may be difficult to elicit.144,145 The early manifestations may be relatively mild and consist of vomiting, polyuria, and dehydration.

In more prolonged and severe cases, Kussmaul respiration is present—and there is an odor of acetone on the breath. Kussmaul respiration may be confused with bronchiolitis or asthma and be treated with steroids or adrenergic agents that worsen diabetes. Abdominal pain and/or rigidity may be present and may mimic appendicitis or pancreatitis. Cerebral obtundation and (ultimately) coma ensue and are related to the degree of hyperosmolarity. Laboratory findings include glucosuria, ketonuria, hyperglycemia, ketonemia, and metabolic acidosis. Leukocytosis is common, and nonspecific serum amylase levels may be elevated. The serum lipase level is usually not elevated. In those with abdominal pain, it should not be assumed that these findings are evidence of a surgical emergency before a period of appropriate fluid, electrolyte, and insulin therapy to correct dehydration and acidosis. The abdominal manifestations frequently disappear after several hours of such treatment.

Definition

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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.

Clinical manifestations of diabetes mellitus

The classic presentation of diabetes in children is a history of polyuria, polydipsia, polyphagia, and weight loss. Polyuria may be heralded by the recurrence of bedwetting in a previously toilet trained child and polydipsia by a child constantly requesting fluids to drink. Unexplained weight loss should raise suspicion of the existence of diabetes that should be confirmed or excluded by measurement of blood glucose concentration first in the postprandial and later in the fasting state. The urine should also be checked for the presence of glucosuria. The duration of these symptoms varies but is often less than 1 month. Most children who are diagnosed with T1DM have been seen by a physician within a week or so of diagnosis. However, diabetes was not considered, and a glucose measurement in blood or urine was not performed.118,119

An insidious onset with lethargy, weakness, and weight loss is also quite common. The loss of weight despite increased dietary intake is readily explicable by the following example. The average healthy 10-year-old child has a daily intake of 2000 or more calories, of which approximately 50% are derived from carbohydrates. With the development of diabetes, daily losses of water and glucose may be as much as 5 L and 250 g, respectively. This represents 1000 calories lost in the urine, or 50% of average daily caloric intake. Therefore, despite the child’s compensatory increased intake of food and water, the calories cannot be utilized, excessive caloric losses continue, and increasing catabolism and weight loss ensue.

Pyogenic skin infections and candidal vaginitis in girls or candidal balanitis in uncircumcised boys are occasionally present at the time of diagnosis of diabetes. They are rarely the sole clinical manifestations of diabetes in children, and a careful history will invariably reveal the coexistence of polyuria, polydipsia, and perhaps weight loss. Ketoacidosis is responsible for the initial presentation of many (about 25% to 40%) diabetic children. Ketoacidosis is likely to be present more often in children younger than 5 years of age because the diagnosis may not be suspected and a history of polyuria and polydipsia may be difficult to elicit.118-126 The early manifestations may be relatively mild and consist of vomiting, polyuria, and dehydration.

In more prolonged and severe cases, Kussmaul respiration is present—and there is an odor of acetone on the breath. Kussmaul respiration may be confused with bronchiolitis or asthma and be treated with steroids or adrenergic agents that worsen diabetes. Abdominal pain or rigidity may be present and may mimic appendicitis or pancreatitis. Cerebral obtundation and (ultimately) coma ensue and are related to the degree of hyperosmolarity. Laboratory findings include glucosuria, ketonuria, hyperglycemia, ketonemia, and metabolic acidosis. Leukocytosis is common, and nonspecific serum amylase levels may be elevated. The serum lipase level is usually not elevated. In those with abdominal pain, it should not be assumed that these findings are evidence of a surgical emergency before a period of appropriate fluid, electrolyte, and insulin therapy to correct dehydration and acidosis. The abdominal manifestations frequently disappear after several hours of such treatment.

5 What are the common signs and symptoms of DKA?

Patients with DKA often present with the symptoms of hyperglycemia, which are polyuria, polydipsia, polyphagia, lassitude, weight loss, and blurry vision. There can be mental status changes ranging from lethargy to deep coma; 20% of patients present in a stuporous state. Nausea, vomiting, and abdominal pain, which are not usually due to definite intra-abdominal pathology, frequently complicate the early course of DKA. Acidosis is also responsible for one of the classic signs of DKA: Kussmaul respirations, which are long, deep, sighing breaths, made in an attempt to compensate for the metabolic acidosis by lowering the arterial PCO2. An odor of decaying apples or fruity gum on the patient's breath is another sign of DKA and is caused by acetone, as the other ketones are odorless.

Patients with DKA are generally volume depleted and have electrolyte disturbances, predominantly a result of hyperglycemia. Hyperglycemia causes glucosuria and, subsequently, an osmotic diuresis with loss of volume and electrolytes. In the average 70-kg man with DKA, there is a 3- to 5-L saline deficiency, a 300- to 500-mEq sodium deficiency, and a 150- to 250-mEq potassium deficiency. Furthermore, patients with DKA are often hypothermic because of the unavailability of substrate to generate heat as well as peripheral vasodilation.

American Diabetes Association: Hyperglycemic crises in diabetes. Diabetes Care 27(Suppl 1):S94–S102, 2004.

Luft's Disease

Luft34 described a 35-year-old woman with symptoms of hyperthyroidism (hyperhidrosis, polydipsia, polyphagia, weight loss) with normal thyroid function. She was nonetheless treated for hyperthyroidism, including thyroidectomy, without the expected results. She was subsequently found to have mitochondria of variable size with increased numbers of cristae. The biochemical defect was a loose coupling of oxidative phosphorylation; for every oxidation of hydrogen, an ATP was not produced from adenosine diphosphate (ADP). Thus, more O2 expenditure was required to achieve a normal amount of energy production. Perioperatively these patients would be at risk for hyperthermia, increased O2 utilization, metabolic acidosis, and hypovolemia.

Complications Prevention

Diabetes

The usual clinical symptoms of diabetes, polyuria and polydipsia, are the direct consequences of the high blood glucose concentration. Weight loss in spite of polyphagia, ketoacidosis, visual changes, skin and urogenital infections, sepsis and pruritus may be present as well. Mild hyperglycemia is usually symptomless. Almost 50% of persons with diabetes do not present these diabetic symptoms. It is therefore quite clear why diagnosis based solely on symptoms bears a very low incidence.

To study the natural history and pathogenesis of diabetes as a whole, the biochemical definition is the only common and stable factor. Hyperglycemia remains therefore the most important factor required for the diagnosis of diabetes.

The chronic hyperglycemia is due to a defective insulin secretion (relative insulin deficiency) and/or insulin resistance (defective insulin action). Chronic exposure to high blood glucose levels induces specific long-term microvascular complications affecting the nerves, the kidneys and the eyes, as well as an increased risk for macrovascular disease, specifically cardiovascular disease (CVD). The diagnostic criteria for diabetes are based on thresholds of glycemia that are associated with microvascular disease, especially retinopathy.