IM Board Review

A 48-year-old man with uncontrolled diabetes

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2. Which of the following hormonal changes underlies the development of diabetic ketoacidosis?

  • Insulin resistance
  • Insulin deficiency
  • Glucagon excess
  • Glucagon deficiency
  • Insulin deficiency and glucagon excess
  • Insulin deficiency and glucagon deficiency

Diabetic ketoacidosis can occur when there is too much glucagon and not enough insulin. Insulin lowers the serum glucose level by promoting glucose uptake in peripheral tissues and by inhibiting gluconeogenesis and glycogenolysis in the liver. Insulin is also anabolic: it inhibits lipolysis in adipocytes and thus decreases the amount of substrate for ketogenesis.

Glucagon is the primary counterregulatory hormone responsible for ketogenesis.6 In the presence of glucagon excess, malonyl CoA production decreases, causing unblocking of carnitine acyltransferase I (CAT I) and allowing beta-oxidation to occur.6

Therefore, the sequence initiating ketogenesis begins with a shift in the ratio of glucagon to insulin, so that there is a relative or absolute excess of glucagon and a deficiency of insulin. A deficiency of insulin accelerates lipolysis, providing more substrate for ketogenesis, while excess glucagon turns on the oxidative sequence for fatty acids in the liver.

Three ketone bodies are produced in diabetic ketoacidosis: two ketoacids (beta-hydroxybutyric acid and acetoacetic acid), and one neutral ketone (acetone). The concentration of insulin required to suppress lipolysis is only one-tenth of that required to promote glucose utilization.7 Diabetic ketoacidosis is uncommon in patients with type 2 diabetes because they typically have enough insulin to inhibit lipolysis (and therefore ketoacid formation) but not enough to promote glucose utilization.


3. Which of the following is not a risk factor for diabetic ketoacidosis in type 2 diabetes mellitus?

  • Acute illness
  • Age > 65
  • Inadequate insulin doses
  • Antipsychotic drugs
  • Ethnicity

Diabetic ketoacidosis is often precipitated by an acute illness such as an infection, cerebrovascular accident, myocardial infarction, or acute pancreatitis.8–12 These acute illnesses induce stress in the body and elevate counterregulatory hormones.

Inadequate insulin doses can also lead to diabetic ketoacidosis.

Drugs that affect carbohydrate metabolism are also risk factors. These include glucocorticoids, thiazide diuretics in high doses (> 50 mg daily), sympathomimetic agents, and second-generation antipsychotic agents (also called “atypical” antipsychotics) such as clozapine (Clozaril) and olanzapine (Zyprexa), although some are worse than others.13,14

Ketosis-prone type 2 diabetes mellitus is more prevalent in African Americans and Hispanics.8,15,16

Age is not a risk factor for developing diabetic ketoacidosis. In fact, diabetic ketoacidosis is the leading cause of morbidity and death in children with type 1 diabetes and can also occur in children with type 2 diabetes, particularly in obese African American adolescents.2


4. Which of the following is most specific in distinguishing type 1 from type 2 diabetes mellitus?

  • C-peptide levels
  • Islet cell antibodies
  • Body mass index
  • Family history
  • Hemoglobin A1c level

Type 1 diabetes is characterized by destruction of pancreatic beta cells, leading to absolute insulin deficiency. The process is usually mediated by autoimmunity; therefore, testing for antibodies to islet cells, glutamic acid decarboxylase, insulin, and tyrosine phosphatase is the most specific way to distinguish type 1 from type 2 diabetes mellitus.

The hemoglobin A1c level correlates with the mean blood glucose level over the previous 8 to 12 weeks. The hemoglobin A1c is typically elevated in both type 1 and type 2 diabetes mellitus and therefore is not a useful distinguishing feature.

C-peptide is made when proinsulin is cleaved into insulin and C-peptide. It is released from endocytic vesicles with insulin in a one-to-one molar ratio. Thus, the level of C-peptide in the blood can show how much insulin is being made by the pancreas. C-peptide levels can help distinguish between type 1 and type 2 diabetes mellitus later in the course of the disease (levels are usually lower in a patient with type 1 diabetes), but they are not as useful early on because they can be normal early in the course of type 1 diabetes.17

A family history of diabetes is more common in type 2 diabetes, but patients with either type 1 or type 2 can have an affected close relative.

Patients with type 2 diabetes are generally overweight, with a body mass index greater than the 85th percentile for their age and sex. In contrast, patients with type 1 diabetes are usually not overweight and often have a recent history of weight loss. There are exceptions, however, and some patients with type 1 diabetes have an elevated body mass index, while some patients with type 2 diabetes are thin.

Although individually, C-peptide, family history, and body mass index are not very specific in distinguishing type 1 from type 2 diabetes mellitus, together they often give the clinician a good idea of the type of diabetes the patient has. In our case, although islet cell antibodies were not drawn, the normal C-peptide level, high body mass index, and family history all support a diagnosis of type 2 diabetes mellitus.

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