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COMMENTARY
Insulin Mutations in Diabetes
The Clinical Spectrum
Benjamin Glaser
S
tudies of monogenic disorders of ␤-cell function
have yielded important information on ␤-cell
physiology and have improved the diagnosis and
treatment of patients with these rare diseases.
These disorders include defects associated with increased
insulin secretion, causing hypoglycemia, and decreased
insulin secretion, resulting in diabetes. The most common
form of monogenic diabetes is so-called maturity-onset
diabetes of the young (MODY) syndrome, causing autosomal dominant non–insulin dependent diabetes appearing
before the age of 25 years. Mutations in six genes can
cause MODY, although in 16 – 45% of cases the genetic
etiology is still unknown (1). Neonatal diabetes mellitus
(NDM) is another form of monogenic diabetes, usually
defined as overt diabetes diagnosed during the first 6
months of life (2). The disease is rare (incidence
1:300,000 –500,000 live births), and ⬃50% of patients have
transient NDM (TNDM), in which the disease remits after
a few months but may reappear months or years later. The
other 50% have permanent NDM (PNDM). In a small
percentage of these, diabetes is part of a complex clinical
syndrome involving organs other than the endocrine pancreas. For those with isolated PNDM, mutations in four
different genes have been identified. Inactivating glucokinase mutations were discovered first, but appear to be
rather rare causes of this syndrome (3). Activating mutations in either of the two subunits of the ␤-cell ATPsensitive K⫹ channel, ABCC8 and KCNJ11, are more
frequently seen (4,5).
In a landmark report last year, Stoy et al. (6) described
16 patients with PNDM caused by insulin gene mutations.
These mutations appear to cause abnormal protein folding
resulting in endoplasmic reticulum (ER) stress, which
activates apoptosis pathways leading to ␤-cell death. Stoy
et al. suggested the need for additional studies in larger
patient populations to discover the true incidence and
clinical spectrum associated with insulin mutations.
In this issue of Diabetes, three groups present their
findings after screening different patient populations for
From the Endocrinology and Metabolism Service, Internal Medicine Department, Hadassah-Hebrew University Medical School, Jerusalem, Israel.
Address correspondence and reprint requests to Benjamin Glaser, MD,
Endocrinology and Metabolism, Hadassah Hospital, P.O.B. 12000, Jerusalem
91120, Israel. E-mail: [email protected].
DOI: 10.2337/db08-0116
ER, endoplasmic reticulum; MODY, maturity-onset diabetes of the young;
NDM, neonatal diabetes mellitus; PNDM, permanent NDM; TNDM, transient
NDM.
See accompanying original articles, pgs. 1034, 1115, and
1131.
© 2008 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
DIABETES, VOL. 57, APRIL 2008
INS mutations. Polak et al. (7) found three missense
mutations in 38 PNDM patients and one in a patient with
childhood-onset nonautoimmune diabetes. Further screening
identified three affected relatives. Molven et al. (8) expanded
the spectrum of disease associated with INS mutations by
screening patients with diabetes onset well after the neonatal
period. They identified one mutation in 92 patients with the
MODY phenotype and one in 124 patients with autoantibodynegative type 1 diabetes, but none in 99 patients with
autoantibody-positive familial type 1 diabetes. Edghill et al.
(9) identified 32 mutation carriers among 279 patients with
PNDM diagnosed before the age of 6 months, 2 more among
86 patients diagnosed between 6 and 12 months, and none in
58 patients diagnosed between 12 and 24 months of age. In
addition, they identified one affected individual among 296
patients with MODY and one in 463 patients with youngonset type 2 diabetes. Taken together, these studies confirm
that the vast majority of patients with INS mutations present
with severe insulin-dependent diabetes within the first 6
months of age. However, a small minority present as late as
20 years of age and can resemble MODY, early-onset type 2
diabetes, or childhood-onset type 1 diabetes. Similarly, the
clinical severity can vary from severe intrauterine insulin
deficiency, causing low birth weight, to diet-responsive diabetes phenotypically indistinguishable from type 2 diabetes.
Reviewing the published data from the last several years,
the genetic etiology of TNDM and PNDM is becoming clearer
(2,10). Currently, the precise genetic cause of TNDM can be
determined in almost all patients, whereas for ⬃40% of
patients with PNDM the genetic etiology is still unknown
(Fig. 1). These studies clearly demonstrate that all patients
with diabetes onset before the age of 6 months should be
investigated for monogenic diabetes, as autoimmune diabetes is exceedingly rare in this age-group. Patients with
autoantibody-negative diabetes diagnosed after the age of 6
months may also warrant genetic investigation, although the
chance of identifying a disease-causing mutation is still low.
These are not the first insulin gene mutations to be
discovered. In the early 1980s, shortly after the discovery of
the insulin gene sequence (11), several patients with insulin
gene mutations were identified. Some mutations affected
insulin-proinsulin processing, resulting in secretion of large
amounts of partially processed proinsulin (12–15), whereas
others appeared to produce normally processed insulin with
subnormal biological activity (16 –18). For most of these,
there was a clear association between the mutation and
marked hyperinsulinemia or proinsulinemia, but not with
diabetes, as some mutation carriers were normoglycemic or
had variable degrees of glucose intolerance.
It is theoretically possible that other insulin gene mutations could result in increased function and thus hypoglycemia, as has been found for glucokinase (19). To study
this, Edghill et al. (9) screened 49 patients with hyperinsulinemic hypoglycemia, but found no INS mutations,
799
INSULIN MUTATIONS IN DIABETES
FIG. 1. Genetic causes of NDM. Approximate relative frequencies of
genetic defects in patients with TNDM and PNDM. The percentages
reported here are approximations gleaned from several recent publications referenced in the text and will vary depending on the population studied and the precise definition of disease state. ‡Several
defects related to abnormal expression of imprinted genes on ch6q
have been associated with TNDM. *Different mutations in these genes
have been found in patients with hyperinsulinism of infancy. §Polymorphisms in these genes have been associated with risk of type 2 diabetes.
suggesting that if such mutations occur they must either
be very rare or result in a phenotype that was not included
in their cohort of patients with hyperinsulinism of infancy.
Data available today suggest that the insulin gene locus
does not contribute significantly to the overall genetic risk
of developing type 2 diabetes, although it should be
emphasized that the majority of published studies were
designed to identify common variants associated with
disease and thus cannot exclude the possibility that a large
number of rare variants within the gene could contribute
significantly to the genetic risk of type 2 diabetes.
Thus, mutations in the insulin gene can cause a spectrum of clinical phenotypes. Mutations affecting receptor
binding or postgolgi processing result in elevated serum
levels of insulin, proinsulin, or proinsulin split products
without necessarily causing hyperglycemia. Mutations affecting ER processing of insulin, in contrast, appear to
result in loss of ␤-cell mass through apoptosis. The severity of the defect, as well as other factors that define the
␤-cell’s capacity to cope with ER stress, determine the rate
of ␤-cell death and thus the age of onset and severity of
clinical disease. At least in some cases, a “window of
opportunity” may exist during which therapeutic intervention, aimed at decreasing ER stress or its effect on ␤-cell
apoptosis, may be possible, thus preserving ␤-cell function
and severe insulin-deficient diabetes.
The importance of identifying specific genetic causes of
monogenic diabetes is twofold. First, these findings improve our understanding of ␤-cell physiology and may
provide important information leading to a better understanding of type 2 diabetes. Second, for the individual, the
identification of the specific genetic cause of disease may
have major therapeutic implications. For example, some
patients with KCNJ11 or ABCC8 mutations can be treated
with oral sulfonylurea drugs, obviating the need for multiple insulin injections and intensive blood glucose monitoring while improving glycemic control and hopefully
preventing or delaying long-term complications (20). For
patients with INS mutations the therapeutic implications
are less obvious, although it may be possible to develop
therapies that increase the relative production of the
normal insulin, improve the folding of the abnormal peptide, or increase the cell’s tolerance for ER stress.
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