understood genetic entity of T2D is atypical diabetes, also called Flatbush diabetes. This is a ketosis-prone diabetes, initially described in African Americans who presented with DKA, but the subsequent disease course more closely resembles classic T2D.26 The underlying pathogenesis is unclear, but studies have shown a transient secretory defect of β-cells at the time of presentation with remarkable recovery of insulin-secretory capacity.27 Ketosis-prone diabetes also has been described in other ethnicities.
Monogenic Diabetes Syndromes
These patients represent a small fraction of diabetes (<5%), which is the result of a single genetic defect and generally presents before the age of 25 years. They usually are negative for the antibodies commonly found in T1D. The two main subtypes of monogenic diabetes are neonatal diabetes and maturity onset diabetes of youth (MODY). When diagnosed within the first 6 months of life, diabetes is called neonatal diabetes, which is not a form of T1D. The diabetes in these neonates may be transient or permanent, with the latter most commonly having a mutation on the gene encoding the Kir6.2 subunit of the β-cell KATP channel. Despite the early onset, these individuals can be well managed with sulfonylureas instead of insulin as children and, if eventually diagnosed later, even as adults. For this reason, all patients diagnosed with diabetes before the age of 6 months should have genetic screening for neonatal diabetes, even if the history of age of onset is discovered decades later.
MODY is a heterogeneous group of antibody-negative, autosomal-dominant inherited, youth-onset disorders of the β-cell. MODY is characterized by impaired insulin secretion but no (or minimal) defects in insulin action. To date, six different gene mutations are identified on different chromosomes, each one resulting in a different clinical entity.28 One of these genes encodes the enzyme glucokinase (associated with MODY 2), whereas the other five loci encode transcription factors. The most common is hepatic nuclear factor 1-a (associated with MODY 3). Differentiating MODY from T1D is important given the autosomal-dominant inheritance of the former and the observation that many of these patients can be controlled with sulfonylureas. Furthermore, those with glucokinase MODY generally need no therapy (except during pregnancy). Specialty commercial lab testing is now available to identify the gene mutations for clinical (nonresearch) diagnosis to accurately diagnose youth who have MODY and to facilitate prompt identification of other potentially affected family members.
Pancreatic Diabetes
Many diseases of the pancreas affect endocrine function. Formally termed “pancreatic diabetes,” the etiologies, degree of insulin sensitivity, and the subsequent risk for hypoglycemia vary.
For example, cystic fibrosis (CF) patients have a high frequency of diabetes called cystic fibrosis–related diabetes (CFRD). This occurs in 40–50% of adult patients with CF.29 Insulin sensitivity is generally normal or only slightly decreased except in the setting of acute illness when insulin resistance can be severe.30 The frequent intervention of lung transplantation requiring use of corticosteroids and calcineurin inhibitors further increases the prevalence of diabetes in this population. Conversely, the diabetes secondary to chronic pancreatitis mainly occurs from the destruction of islet cells by pancreatic inflammation. There is also an idiopathic variety of chronic, calcific pancreatitis associated with malnutrition that has been termed “tropical chronic pancreatitis.” Both of these latter forms of chronic pancreatitis also are associated with glucagon deficiency and thus more marked sensitivity to insulin with increased risks of hypoglycemia associated with insulin therapy.
Hereditary hemochromatosis is another etiology of pancreatic diabetes, with up to 23% of hemochromatosis patients in one study diagnosed with diabetes.31
Surgical pancreatectomy is particularly common in hospitals with busy oncology centers. Immediately after surgery, insulin deficiency in these patients can be reasonably easy to control with basal-bolus insulin therapy. These patients, however, are extremely prone to the risk of devastating hypoglycemia because of glucagon deficiency, and reducing insulin dosing by 20–25% at discharge from the hospital is suggested.
Ideally, patients scheduled for pancreatectomy should meet with a diabetes team or endocrinologist before the surgery and focused diabetes education is needed after this procedure. Because the pancreatectomy is due to a malignancy (or in some cases pancreatic dysplasia32), the diabetes often is not the main focus of the patient or the family. Especially for those patients who have a good prognosis, the importance of good glycemic control and avoidance of hypoglycemia, even more so than the newly diagnosed patient with T1D, should be stressed. The glucagon deficiency, besides leading to abnormal glucose counterregulation, also results in overall increased insulin sensitivity, meaning extra precaution is required for exercise. Although exact data are not available, there are anecdotal reports of death resulting from hypoglycemia in this population possibly related to physical activity, lack of blood glucose testing, alcohol, or a combination. Continuous glucose monitoring should be strongly considered for these patients.
Drug-Induced Diabetes
Many drugs are known to cause diabetes. Some drugs, such as streptozotocin and IV pentamidine can permanently destroy pancreatic β-cells. More commonly, the ubiquitously useful glucocorticoid therapies (including IV, oral, intra-articular, inhaled, and even topical) can result in hyperglycemia or frank diabetes. Glucocorticoids cause hyperglycemia by increasing insulin resistance by several mechanisms, including inducing an increase in visceral fat and direct actions on muscle and liver resulting in decreased insulin activity. Atypical antipsychotics also can result in diabetes in part because of the effects of increasing appetite and food intake resulting in obesity, although the exact mechanisms are complex.33 DKA has been described as resulting from these agents and should be considered by the health-care providers when someone taking one of these medications presents with this metabolic emergency.34 Table 2.4 lists medications often used in the hospital that can cause hyperglycemia or diabetes.
Table 2.4—Drugs Often Used in the Hospital That Can Cause Hyperglycemia or Diabetes
Antibiotics
—Quinolones
Gantifloxicin (can also cause hypoglycemia)
Levofloxicin
Atypical antipsychotics
—Most risky
Clozapine
Olanzapine
—Intermediate
Paliperidone
Risperidone
β-Blockers (carvedilol not associated with hyperglycemia)
—Atenolol
—Metoprolol
—Propranolol
Calcineurin inhibitors
—Cyclosporin
—Sirolimus
—Tacrolimus
Corticosteroids
Diazoxide
Nicotinic Acid
Protease inhibitors
Thiazide and thiazide-like diuretics
Lipodystrophic Diabetes
Lipodystrophies are heterogeneous-heterogeneously acquired or inherited disorders characterized
