Health Questions and Answers

DIABETES MELLITUS

List the three main categories of diabetes mellitus (DM).

  • Type 1 (previously called insulin-dependent DM or juvenile-onset DM)
  • Type 2 (previously called non-insulin-dependent DM or adult-onset DM)
  • Gestational diabetes (diabetes diagnosed in pregnancy)

Describe type 1 DM.
Type 1 DM accounts for approximately 5-10% of patients and is generally due to autoimmune destruction of the pancreatic beta-cells, leading to absolute insulin deficiency. Although typically diagnosed in patients before age 30, it can present at any age due to variability in the rate of beta-cell destruction.

What are the major characteristics of type 2 DM?
The majority of patients have type 2 DM, which is associated with insulin resistance and relative insulin deficiency. Most patients are obese (predominantly abdominal accumulation). Type 2 DM is diagnosed in adulthood, and patients are not prone to develop ketoacidosis except in association with the stress from another illness.

What is gestational DM?
Gestational DM, which is diagnosed during pregnancy, occurs in approximately 4% of pregnant women and usually presents in the second or third trimester when insulin resistance normally occurs. It is associated with increased fetal morbidity and mortality. Glucose tolerance usually returns to normal after delivery, but 30-40% of women with gestational DM develop type 2 DM within 10 years.

Summarize other specific types of DM.
Other specific types of DM include genetic defects in beta-cell function, also known as maturity-onset diabetes of the young, genetic defects in insulin action (i.e., mutations in the insulin receptor), diseases of the exocrine pancreas (e.g., hemochromatosis, neoplasm, cystic fibrosis), endocrinopathies (e.g., Cushing’s syndrome, acromegaly, somatostatinoma, glucagonoma), drug-induced DM (e.g., pentamidine, glucocorticoids, alpha interferon), infections, and other rare genetic disorders.

Summarize the two sets of criteria in routine clinical use for the diagnosis of DM.

  • Symptoms of diabetes plus casual plasma glucose (PG) concentration ≥ 200 mg/dL (11.1 mmol/L). Casual is defined as any time of day without regard to last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. or
  • Fasting PG ≥ 126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hours.

What caveat applies to both sets of criteria?
In the absence of unequivocal hyperglycemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day.

What is the oral glucose tolerance test (OGTT)?
The OGTT is a specialized test for the diagnosis of DM. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 gm of anhydrous glucose dissolved in water. A positive test is defined as 2-hour PG ≥ 200 mg/dL (11.1 mmol/L). The OGTT is an accepted method for diagnosing DM; it is just not used routinely because it is more cumbersome than the other criteria.

What is the role of hemoglobin A1c in the diagnosis of DM?
Hemoglobin A1c is not used to diagnose DM.

What is “pre-diabetes”?
Pre-diabetes refers to an intermediate group of people who have glucose values too high to be considered normal but do not fit the criteria for the diagnosis of DM. They are at high risk of developing DM. This group includes patients with impaired glucose tolerance (IGT) and impaired fasting glucose (IFG).

Define IGT and IFG.
IGT is defined as a 2-hour postload glucose of 140-199 mg/dL (7.8-11.1 mmol/L), using the OGTT. IFG is defined as fasting PG of 100-125 mg/dL (5.6-6.9 mmol/L). IGT and IFG are not truly disease entities but are associated with the metabolic syndrome and a high risk of developing DM and cardiovascular disease.

List the characteristics of the metabolic syndrome.

The metabolic syndrome refers to a constellation of signs and symptoms that are associated with an increased risk of cardiovascular disease and include:

  1. Pre-diabetes or diabetes (hyperinsulinemia)
  2. Abdominal (central) obesity
  3. Hypertension
  4. Atherosclerosis
  5. Polycystic ovarian syndrome
  6. Atherogenic dyslipidemia (elevated triglycerides, apolipoprotein B, small dense LDL and low HDL)
  7. Altered coagulant state (impaired fibrinolysis, increased plasminogen activator inhibitor-1)
  8. Proinflammatory state (elevated C-reactive peptide)

THREE KEY POINTS: DIAGNOSTIC FEATURES OF METABOLIC SYNDROME (THREE OR MORE OF THE FOLLOWING)

  • Abdominal obesity (waist circumference: men > 40 inches (102 cm), women > 35 inches (88 cm)
  • Hypertriglyceridemia (≥ 150 mg/dL)
  • Low HDL cholesterol (men < 40 mg/dL, women < 50 mg/dL)
  • Hypertension (≥ 130/85 mmHg)
  • Fasting hyperglycemia (≥ 110 mg/dL)

Describe the pathophysiology of diabetic ketoacidosis (DKA).
The pathogenesis of DKA involves an increase in counter-regulatory hormones (catecholamines, cortisol, glucagon, and growth hormone), accompanied by insulin deficiency. All of these hormonal factors contribute to increased hepatic and renal glucose production and decreased peripheral glucose utilization. These hormonal changes also serve to enhance lipolysis and ketogenesis as well as glycogenolysis and gluconeogenesis and serve to worsen hyperglycemia and acidosis. Lipolysis leads to increased free fatty acid synthesis for ultimate conversion by the liver to ketones. This state is associated with increased production and decreased utilization of glucose and ketones. Glucosuria leads to osmotic diuresis and dehydration that is associated with reduced renal function and worsening acidosis.

List the clinical features of DKA.
Clinical features vary with the severity of DKA:

  1. polydipsia
  2. polyphagia
  3. polyuria
  4. severe dehydration
  5. altered mental status (ranges from normal to coma)
  6. gastrointestinal distress (nausea, vomiting, abdominal pain)
  7. weight loss
  8. weakness

What physical exam findings are associated with DKA?
Physical exam findings also vary with the severity of DKA: dehydration, poor skin turgor, Kussmaul breathing (deep, sighing respiration) mental status changes (wide range), hypotension, tachycardia, musty (fruity) breath, hyporeflexia, and hypothermia. Untreated DKA can progress to coma, shock, and death.

Summarize the lab data associated with DKA.
Lab data, which vary with the severity of DKA, include PG > 250 mg/dL, arterial pH < 7.3, serum bicarbonate < 18 mEq/L, positive serum and urine ketones, and elevated anion gap (> 10-12). Although the above lab results are diagnostic for DKA, one may see other abnormalities, including: elevated blood urea nitrogen and creatinine with dehydration, leukocytosis, low serum sodium, and elevated serum potassium due to extracellular shifting caused by insulin deficiency.

How is DKA managed?
In general, successful treatment of DKA includes fluid resuscitation, insulin therapy, and careful monitoring and correction of electrolyte imbalances. It is extremely important to identify precipitating factor(s) when possible. The most common precipitating factor is infection. The hospitalized patient should have appropriate bacterial cultures (e.g., blood, urine) and antibiotic therapy if infection is suspected.

What factors other than infection may precipitate DKA?
Other precipitating factors include myocardial infarction, stroke, pancreatitis, trauma, alcohol abuse, or medications (particularly inadequate insulin therapy).

Should patients with DKA be hospitalized?
Hospitalization depends on the severity of DKA, and very mild DKA in experienced patients with type 1 DM can be managed in the outpatient setting. Most patients, however, require hospitalization for IV fluid management, insulin (IV insulin infusion is the treatment of choice), and correction of electrolytes (sodium, potassium, phosphate, bicarbonate).

What principle should be kept in mind when patients are transitioned from IV to subcutaneous (SC) insulin?
The SC insulin must be given prior to discontinuing IV insulin (usually 1-2 hours to allow for adequate plasma insulin levels) to avoid return of hyperglycemia and/or DKA.

What is hyperglycemic hyperosmolar nonketotic syndrome (HHNS)?
Patients with HHNS present with severe hyperglycemia, profound dehydration, and some degree of alteration in mental status (50%). Typically patients have type 2 DM and mild renal impairment. The plasma glucose is frequently very elevated (> 600 mg/dL). Ketosis is usually only very mild or absent. Patients typically have severe dehydration, and plasma hyperosmolarity (> 340 mOsm/L) is one hallmark of this condition.

How is HHNS treated?
Treatment consists of aggressive fluid replacement, insulin, and correction of electrolyte disturbances. As with DKA, a search for the precipitating factor is warranted.

What is hemoglobin A1c?
Hemoglobin A1c (glycohemoglobin) is glycosylated hemoglobin and is used as a measure of average serum glucose concentrations over the prior 2-3 months.

How is hemoglobin A1c used clinically?
Hemoglobin A1c is an overall indicator of glycemic control. It should be measured biannually in patients who meet treatment goals (typically A1c < 7%) or quarterly in patients whose therapy is actively changing. Although an ideal goal for A1c is < 7%, this goal must be individualized. Less intensive goals may be indicated in patients with frequent hypoglycemia, and more intensive goals may be desired in some patients to further reduce diabetes complications.

What are the currently recommended goals for glycemic control in patients with DM?

  • Hemoglobin A1c < 7%
  • Preprandial glucose 90-130 mg/dL
  • Postprandial glucose < 180 mg/dL

Summarize the management of cardiovascular risk factors and screening guidelines for coronary disease in patients with diabetes mellitus.

  • Blood pressure control. The goal is < 130/80 mmHg. Therapy should be individualized for each patient. First-line agents include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. Second-line agents include diuretics, beta blockers, and dihydropyridine calcium channel blockers.
  • Smoking cessation.
  • Lipid management. Test annually or more frequently if patient has not met the following goals: LDL < 100 mg/dL, triglycerides < 50 mg/dL, and HDL > 40 mg/dL.
  • Consider aspirin therapy for primary or secondary prevention.
  • Consider screening for coronary artery disease.
  • Fenofibrates

What guidelines are recommended for screening of diabetic nephropathy?
Screen for microalbuminuria annually with spot albumin-to-creatinine ratio, and treat if detected. Microalbuminuria is defined as 30-299 μg albumin/mg creatinine and must be confirmed on repeated exams. Clinical albuminuria is defined as ≥ 300 μg albumin/mg creatinine. Start screening patients with type 1 DM when they have had DM for > 5 years and patients with type 2 DM at the time of diagnosis.

Summarize the screening recommendations for diabetic retinopathy.
Patients with type 1 DM should receive a comprehensive dilated eye exam within 3-5 years of diagnosis and annually thereafter. Patients with type 2 DM should receive a comprehensive dilated exam at the time of diagnosis and annually. The eye care specialist may determine altered timing of follow-up exams.

How are patients screened for diabetic neuropathy?
Patients should be assessed with monofilament sensory testing. Perform a good foot exam, and educate patients about foot care.

What other educational elements are important in the management of DM?
All diabetic patients should be educated about nutrition and lifestyle modifications.

Summarize the immunization guidelines for diabetic patients.
Annual influenza vaccine should be given to all patients with DM greater than age 6 months. Pneumococcal vaccine is recommended for all diabetic adults at least once.

Describe the different types of insulin.
Insulin

Where is insulin cleared?
Approximately 50% of insulin is cleared via first pass through the liver. Once insulin is in the periphery, 30% is cleared by the kidney. Intravenous insulin has an extremely short half-life regardless of the type of insulin used (e.g., regular or Lispro). As soon as the insulin IV infusion is discontinued, it is generally cleared quickly from the circulation.

List the chronic complications of DM.

  1. Microvascular
  • Neuropathy (painfulparesthesias, autonomic neuropathy)
  • Retinopathy (nonproliferative and proliferative retinopathy, blindness)
  • Nephropathy (spectrum of disease from microalbuminuria to end-stage renal disease)

2. Macrovascular (cardiovascular and peripheral vascular disease)

  • Nonhealing ulcers, amputations
  • Hypertension
  • Dyslipidemia

What are the symptoms of hypoglycemia?
Symptoms can be divided into two categories: adrenergic (due to excess secretion of epinephrine) and neuroglycopenic (due to cerebral dysfunction). Patients with DM typically develop symptoms of hypoglycemia when blood glucose values fall below 50-60 mg/dL but severity of symptoms can vary with the individual. Additionally, some fasting individuals (particularly women) without DM can be completely asymptomatic with glucose values around 50 ng/dL.
Hypoglycemia

Describe hypoglycemia-associated autonomic failure.
Hypoglycemia-associated autonomic failure refers to a syndrome of inappropriate response to hypoglycemia that occurs in patients with DM. Under normal physiologic conditions, hypoglycemia induces a reduction in insulin levels and an enhancement of glucagon and epinephrine secretion, both of which serve to defend against continued hypoglycemia. Patients with type 1 DM and many patients with type 2 DM have defective glucose counter-regulation. Since they cannot reduce exogenous insulin levels and have impaired glucagon and epinephrine responses to hypoglycemia, they become prone to severe iatrogenic hypoglycemia. Additionally, they frequently have attenuated sympathoadrenal responses to hypoglycemia. Hypoglycemia-associated autonomic failure is induced by hypoglycemia and reversed by avoidance of hypoglycemia.

What is hypoglycemic unawareness?
Hypoglycemic unawareness refers to hypoglycemia that occurs unnoticed by the patient because it is not associated with any adrenergic symptoms. It is not uncommon for such patients to have exceedingly low glucose levels without cognitive impairment or other symptoms. They may go into an altered mental state without warning due to the lack of associated adrenergic symptoms.

What is the diagnostic approach to hypoglycemia in patients without diabetes?
First, hypoglycemia should be established using Whipple’s triad: presence of symptoms consistent with hypoglycemia (such as sweating, hunger, palpitations, and weakness), documented low plasma glucose at the time of symptoms, and relief of symptoms when the plasma glucose concentration is raised to normal levels. Hypoglycemia in the fasting state is typically more clinically concerning than reactive (postprandial) hypoglycemia. Although the exact criteria are debated, glucose levels of < 50 mg/dL in men and < 40 mg/dL in women are generally accepted as indicative of hypoglycemia.

Summarize the differential diagnosis of adult hypoglycemia not related to diabetes.

  • Drug-induced or factitious hypoglycemia. It is important to rule out exposure to exogenous insulin and oral antidiabetic agents, particularly sulfonylureas. Other drugs associated with hypoglycemia include ethanol (inhibits gluconeogenesis), salicylates, sulfonamides, pentamidine, monoamine oxidase (MAO) inhibitors, and quinine.
  • Critical illness, including liver and renal failure.
  • Adrenal insufficiency (lack of the counter-regulatory hormone cortisol).
  • Insulinoma: tumor of the pancreatic beta cell that produces too much insulin.
  • Non-beta-cell tumors, including mesenchymal tumors such as fibrosarcoma, mesothelioma, and leiomyosarcoma, that produce insulin-like growth factor I (IGF-I) or IGF-II.
  • Insulin or insulin receptor autoantibodies (rare).

How do you distinguish between endogenous and exogenous hyperinsulinemia?
Insulin and C-peptide levels are helpful to distinguish between endogenous and exogenous hyperinsulinemia since insulin and its cleavage product C-peptide are secreted by the pancreatic beta cell in equimolar amounts. If a patient is getting exogenous insulin, insulin levels will be high and C-peptide levels low. Both values are elevated in patients with surreptitious sulfonylurea use since these drugs stimulate release of endogenous insulin and C-peptide. Sulfonylurea blood levels can also help rule out drug-induced hypoglycemia in this setting.

List the most common pancreatic endocrine tumors.
These tumors are derived from the islet cells of the pancreas and are named for the hormones that they secrete. They are listed below along with their clinical presentations:

  1. Insulinoma (secretes insulin): hypoglycemia.
  2. Gastrinoma (secretes gastrin): Zollinger-Ellison syndrome, associated with excess gastric acid secretion and peptic ulcer disease.
  3. Glucagonoma (secretes glucagon): DM, weight loss, anemia, necrolytic migratory erythema.
  4. Somatostatinoma (secretes somatostatin): somatostatin inhibits secretion of insulin gastric acid and pancreatic enzymes, leading to diabetes, weight loss, hypochlohydria, steatorrhea, and gallstones.
  5. VIPoma (secretes vasoactive intestinal peptide): watery diarrhea, hypokalemia, achlorhydria.
  6. PPoma (secretes pancreatic polypeptide alone or in combination with other pancreatic peptides): watery diarrhea.

Identify the hereditary syndrome associated with pancreatic tumors.
Multiple endocrine neoplasia syndromes (MEN) are characterized by neoplastic transformation in multiple endocrine glands. MEN type 1 (MEN1) is associated with pancreatic tumors. MEN1 is now known to be caused by a mutation in the tumor suppressor MEN1 gene, whose product is named menin.

What are the components of MEN1?
Components of MEN1 include the 3 Ps:

  1. Pituitary tumors (most commonly prolactinoma)
  2. Primary hyperparathyroidism (typically due to parathyroid hyperplasia)
  3. Pancreatic tumors (most commonly gastrinoma, followed by insulinoma)

What are MEN2A and MEN2B?
MEN2A and MEN2B are due to activating mutations of the RET proto-oncogene. MEN2A includes neoplasms of the thyroid (medullary thyroid carcinoma), parathyroid (primary hyperparathyroidism), and adrenal gland (pheochromocytoma). MEN2B includes medullary thyroid carcinoma, pheochromocytoma, and mucosal neuromas.

References
USEFUL ENDOCRINE-RELATED WEB SITES
The Endocrine Society: www.endo-society.org
Uptodate Reference: www.uptodate.com
Endotxt.org (Web-based source of information about endocrine diseases directed to physicians)
American Association of Clinical Endocrinologists: www.aace.com
Pituitary Society: www.pituitarysociety.org
American Thyroid Association: www.thyroid.org
American Diabetes Association: www.diabetes.org
American Society for Bone and Mineral Research: www.ASBMR.org
National Osteoporosis Foundation: www.nof.org
American Heart Association: www.americanheart.org

BIBLIOGRAPHY

  • Fenofibrate Intervention and Event Lowering in Diabetes http://www.fieldstudy.info/investigators/index.asp
  • Standards of Medical Care in Diabetes—2012 http://care.diabetesjournals.org/content/35/Supplement_1/S11.full
  • Braverman LE, Utiger RD (eds): Werner and Ingbars’ Thyroid. A Fundamental and Clinical Text. Philadelphia, Lippincott Williams & Wilkins, 2000.
  • Larson PR, et al: Williams Textbook of Endocrinology, 10th ed. Philadelphia, W.B. Saunders, 2003.

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