Table 20.5 ) are uncommon examples of the diabetes occurring as a result of loss-of-function mutations within a single gene. Monogenic causes of diabetes include primary defects in beta cell function and insulin receptor signaling. Monogenic diabetes can be classified based on age of onset into congenital early onset diabetes (manifesting in the neonatal period) and maturity onset diabetes of the young (MODY), which develops beyond the neonatal period but usually before 25 years of age. Some of the underlying causes of congenital diabetes include mutations of the insulin gene itself, and mutations in mitochondrial DNA that lead to a syndrome of maternally inherited diabetes and bilateral deafness (the maternal pattern of inheritance being a sine qua non of mitochondrial DNA mutations). Rare instances of insulin receptor mutations that affect receptor synthesis, insulin binding, or downstream signal transduction can cause severe insulin resistance, accompanied by hyperinsulinemia (due to lack of feedback inhibition) and congenital diabetes. In contrast, MODY is caused by mutations in genes encoding factors driving beta cell function (see
Table 20.5 ), and at least superficially, tends to resemble usual type 2 diabetes in many of its clinical features. Thus, it is not surprising that the diagnosis of MODY is often missed in individuals who harbor an underlying pathogenic mutation.
In addition to Types 1 and 2 and monogenic forms of diabetes, the other broad subtypes include secondary diabetes and pregnancy-induced (“gestational”) diabetes. Secondary diabetes arising as a result of endocrinopathies (for example, Cushing syndrome or growth hormone excess) have been described in relevant portions of this chapter. Here, we will briefly discuss a form of secondary diabetes arising as a result of a variety of chronic exocrine pancreatic diseases (“pancreatogenic” diabetes), and the important subtype known as gestational diabetes.
Gestational diabetes. Approximately 5% of pregnancies occurring in the United States are complicated by hyperglycemia. Pregnancy is a “diabetogenic” state in which the prevailing hormonal milieu favors a state of insulin resistance. In some euglycemic pregnant women this can give rise to gestational diabetes. Women with pregestational diabetes (where hyperglycemia is already present in the periconception period) have an increased risk for stillbirth and congenital malformations in the fetus (Chapter 7). Therefore, tight glycemic control is needed early in pregnancy to prevent congenital defects, and through the later trimesters of pregnancy to prevent fetal overgrowth (macrosomia). The latter occurs because maternal hyperglycemia can induce compensatory secretion of insulin-like growth factors in the fetus. Most pregnant women who develop gestational diabetes require insulin for glycemic control. Gestational diabetes typically resolves following delivery; however, there is an elevated risk for developing outright diabetes within the next ten years (highest in the first five years after pregnancy), after which the risk of diabetes reverts to that of women without antecedent gestational diabetes.
Pancreatogenic diabetes is defined as hyperglycemia occurring as a result of a disorder of the exocrine pancreas (see
Table 20.5 ). Pancreatogenic diabetes is heterogeneous, with underlying causes ranging from cystic fibrosis, to chronic pancreatitis, to pancreatic adenocarcinoma. In fact, evidence suggests that approximately 1% of new-onset diabetes in older adults is actually a manifestation of an occult pancreatic adenocarcinoma.
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It is difficult to discuss with brevity the diverse clinical presentations of diabetes mellitus. We will discuss the most common initial presentation or mode of diagnosis for each of the two major subtypes, followed by a discussion of acute and chronic complications of diabetes.