Classification of Diabetes Mellitus and Genetic Diabetic Syndromes PDF

Classification of diabetes mellitus and genetic diabetic syndromes
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Official reprint from UpToDate

www.uptodate.com 2016 UpToDate

Author
David K McCulloch, MD
Section Editors
David M Nathan, MD
Joseph I Wolfsdorf, MB, BCh
Deputy Editor
Jean E Mulder, MD
Disclosures: David K McCulloch, MD Nothing to disclose. David M Nathan, MD Nothing to disclose. Joseph I Wolfsdorf, MB, BCh Nothing
to disclose. Jean E Mulder, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2015. | This topic last updated: Oct 06, 2014.
INTRODUCTION Type 2 diabetes accounts for over 90 percent of cases of diabetes in the United States, Canada,
and Europe; type 1 diabetes accounts for another 5 to 10 percent, with the remainder due to other causes (table 1).
New information has led to increased understanding of genetic defects related to diabetes. Monogenic causes of type 2
diabetes (eg, those causing maturity onset diabetes of the young) represent only a small fraction of cases, and
commonly inherited polymorphisms individually contribute only small degrees of risk for, or protection from, diabetes.
Most of the genetic risk for type 2 diabetes results from complex polygenic risk factors.
The etiologic classification of diabetes mellitus will be reviewed here. The definition and diagnostic criteria for diabetes
mellitus are discussed separately. (See "Clinical presentation and diagnosis of diabetes mellitus in adults".)
TYPE 1 DIABETES Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to absolute
insulin deficiency. This is usually due to autoimmune destruction of the beta cells (type 1A). Testing for islet cell
antibodies (ICA) or other islet autoantibodies (antibodies to glutamic acid decarboxylase [GAD] 65, insulin, and to the
tyrosine phosphatases, insulinoma-associated protein 2 [IA-2] and IA-2 beta, and zinc transporter ZnT8) in serum may
be helpful if establishing the diagnosis is important; a positive result is indicative of immune-mediated or type 1A
diabetes [1]. However, the absence of pancreatic autoantibodies does not rule out the possibility of type 1 diabetes.
Some patients with absolute insulin deficiency have no evidence of autoimmunity and have no other known cause for
beta cell destruction. They are said to have idiopathic or type 1B diabetes mellitus. (See "Pathogenesis of type 1
diabetes mellitus".)
The current American Diabetes Association (ADA) classification of diabetes mellitus does not reflect the clinical
heterogeneity of patients with diabetes and the emergence of the concept that early beta cell dysfunction is likely to be
a primary defect in the pathophysiology of diabetes, regardless of "type." Other classification schemes have been
proposed, accounting for beta cell autoimmunity, beta cell function, clinical features, and body weight. The high
prevalence of overweight/obesity in the population has further complicated classification systems with an added
element of insulin resistance even in type 1 diabetes. (See "Syndromes of ketosis-prone diabetes mellitus", section on
'Classification'.)
It is anticipated that other subtypes of type 1 (and type 2 diabetes) will become more clearly defined in the future.
Latent autoimmune diabetes in adults (LADA) Older studies in predominantly Scandinavian populations have
suggested that as many as 7.5 to 10 percent of adults in populations with a high prevalence of type 1 diabetes and with
apparent type 2 diabetes may have circulating autoantibodies directed against pancreatic beta cell antigens (islet-cell
antibodies [ICA] or GAD65) [2-4]. The prevalence of LADA is almost certainly lower in the more diverse United States
population. These adults do not require insulin at diagnosis but progress to insulin dependence after several months to
years. This entity is sometimes referred to as "latent autoimmune diabetes in adults" (LADA) and may account for a
very small fraction of all cases of diabetes [5-7].
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In genotyping analyses, LADA shares genetic features of both type 1 and type 2 diabetes [8-10]. As an example, in
one analysis, patients with LADA shared an increased frequency of risk for an HLA-DQB1 genotype with patients with
type 1 diabetes and for a variant in the transcription factor 7-like 2 (TCF7L2) gene with patients with type 2 diabetes
[8]. The variant in TCF7L2 has been shown to increase the risk for type 2 diabetes in several populations, and the
effect size was similar for LADA and type 2 diabetes [9]. Thus, LADA appears to be on the spectrum of insulin
deficiency between type 1 and type 2 diabetes. (See "Pathogenesis of type 1 diabetes mellitus", section on
'Autoimmunity' and "Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)
Patients with LADA are a heterogeneous group of patients with variable titers of antibodies, body mass index (BMI),
and frequency of progression to insulin independence [11]. Patients with high compared with low titers of GAD65
antibodies usually have a lower BMI, less endogenous insulin secretion (as measured by stimulated serum C-peptide
concentrations), and progress more quickly to insulin dependence [11,12]. Thus, the presence and titers of anti-GAD
antibodies (or ICA) can help to identify patients thought to have type 2 diabetes, who are likely to respond poorly to
oral hypoglycemic drug therapy, require insulin, and to be at increased risk for developing ketoacidosis [4,5,11-13].
Studies are underway to determine whether early treatment with insulin or use of immunomodulator therapy can prevent
disease progression [6]. (See 'Distinguishing type 1 from type 2 diabetes' below.)
TYPE 2 DIABETES Type 2 diabetes is by far the most common type of diabetes in adults and is characterized by
hyperglycemia and variable degrees of insulin deficiency and resistance. It is a common disorder whose prevalence
rises markedly with increasing degrees of obesity. Insulin resistance and insulin deficiency can arise through genetic or
environmental influences, making it difficult to determine the exact cause in an individual patient. In addition,
hyperglycemia itself can impair pancreatic beta cell function and exacerbate insulin resistance. (See "Pathogenesis of
type 2 diabetes mellitus".)
DKA in type 2 diabetes Patients with type 2 diabetes typically present with hyperglycemia, although ketoacidosis
can occur. Diabetic ketoacidosis (DKA) in type 2 diabetes occurs by several mechanisms, similar to those in type 1
diabetes. The stress of infection or other illness causes increased secretion of counterregulatory hormones and further
increases insulin resistance. The already impaired insulin secretion is unable to respond to the increased demand,
leading to hyperglycemia, which may further impair insulin secretion via glucose toxicity. (See "Syndromes of
ketosis-prone diabetes mellitus".)
DISTINGUISHING TYPE 1 FROM TYPE 2 DIABETES It is occasionally difficult to distinguish between type 1 and
atypical presentations of type 2 diabetes. Patients with type 1 diabetes have an absolute requirement for insulin
therapy. However, many patients with type 2 diabetes lose beta cell function over time and require insulin for glucose
control. Thus, need for insulin per se does not distinguish between type 1 and type 2 diabetes. While it is known that
diabetic ketoacidosis (DKA) can occur in the presence of complete insulin deficiency, and it is not a typical feature of
type 2 diabetes, some patients with type 2 diabetes develop DKA under certain circumstances (usually severe infection
or other illness). Thus, ketoacidosis cannot be relied upon as an absolute indicator that the patient has type 1 diabetes
or that long-term insulin therapy will be required. (See "Syndromes of ketosis-prone diabetes mellitus".)
In addition, patients with type 1 diabetes may coincidentally have pathophysiologic elements of type 2 diabetes. In the
past, poor metabolic control of type 1 diabetes prevented most of these patients from gaining weight. Intensive therapy
now commonly used to manage type 1 diabetes has resulted in approximately 20 to 30 percent of type 1 diabetic
patients becoming overweight or obese. Insulin resistance and other features of type 2 diabetes may be exhibited in
overweight patients with type 1 diabetes, especially those who also have a family history of type 2 diabetes [14].
The presence of antibodies to glutamic acid decarboxylase (GAD), islet cell, insulin, the tyrosine phosphatases
(insulinoma-associated protein 2 [IA-2] and IA-2 beta), and zinc transporter (ZnT8) in patients with presumed type 2
diabetes can identify patients who may have type 1 diabetes (latent autoimmune diabetes in adults [LADA]) and are
more likely to require insulin [4,5,12,13,15]. Based upon a review of clinical features in 102 adult diabetic patients who
did not initially require insulin but who were positive for anti-GAD antibodies, a screening tool was developed to identify
adult patients with newly diagnosed diabetes who should be considered for antibody testing [16]. These features
included: age of onset <50 years, acute symptoms, body mass index (BMI) <25 kg/m2, and personal or family history
of autoimmune disease. The presence of two or more criteria had a 90 percent sensitivity and 71 percent specificity for
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identifying patients positive for anti-GAD antibodies. (See "Prediction of type 1 diabetes mellitus", section on
'Immunologic markers'.)
We often measure autoantibodies when the diagnosis of type 1 or type 2 diabetes is uncertain by clinical presentation
(ie, thin patient with poor response to initial therapy with sulfonylureas or metformin, personal or family history of
autoimmune disease). Measuring more than one antibody will increase the likelihood of a positive value, but it is also
more costly. Some clinicians measure two antibodies (ie, islet cell and GAD65), whereas others measure three (insulin,
GAD65, and IA-2 or GAD65, IA-2, and ZnT8). Insulin antibodies should not be measured if the patient has received
insulin therapy for 2 weeks because this will generate insulin antibodies. If one or more of the antibodies is present,
and especially if two or more are positive, the patient should be presumed to have type 1 diabetes and should be
treated with insulin replacement therapy, as these patients respond poorly to diet and oral hypoglycemic drug therapy.
In addition, during early stages in the development of type 1 diabetes, intensive insulin therapy prolongs beta cell
function [17].
Given the risk of ketoacidosis, insulin should also be started in any patient, regardless of whether they are thought to
have type 1 or type 2 diabetes, who is catabolic (weight loss or dehydration in the setting of hyperglycemia) or who has
evidence of increased ketogenesis (ketonuria or acidosis). (See "Management of blood glucose in adults with type 1
diabetes mellitus" and "Insulin therapy in type 2 diabetes mellitus", section on 'Insulin as initial therapy'.)
GENETIC DEFECTS As the human genome is further explored, it is likely that multiple genetic anomalies at different
loci will be found that confer varying degrees of predisposition to type 1 and type 2 diabetes. Polymorphisms of multiple
genes are reported to influence the risk of type 1A diabetes, including genes in both the major histocompatibility
complex (MHC) and elsewhere in the genome, but only human leukocyte antigen (HLA) alleles have a large effect,
followed by insulin gene polymorphisms, and PTPNN22. (See "Pathogenesis of type 1 diabetes mellitus", section on
'Genetic susceptibility'.)
Numerous common polymorphisms (approximately 50 to date) weakly contribute to the risk for or protection from type
2 diabetes. The genes encode proteins that cause alterations in several pathways leading to diabetes, including
pancreatic development, insulin synthesis, processing, and secretion; amyloid deposition in beta cells; cellular insulin
resistance; and impaired regulation of gluconeogenesis. Monogenic causes of type 2 diabetes represent only a small
fraction of cases and commonly inherited polymorphisms individually contribute only small degrees of risk for, or
protection from, diabetes. Most of the genetic risk for type 2 diabetes results from complex polygenic risk factors. (See
"Pathogenesis of type 2 diabetes mellitus", section on 'Genetic susceptibility'.)
Maturity onset diabetes of the young Maturity onset diabetes of the young (MODY) is a clinically heterogeneous
disorder characterized by non-insulin dependent diabetes diagnosed at a young age (<25 years) with autosomal
dominant transmission and lack of autoantibodies [18]. MODY is the most common form of monogenic diabetes,
accounting for 2 to 5 percent of diabetes [19,20]. The population prevalence of MODY in the United Kingdom is
estimated to be 68 to 108 cases per million [21]. These patients are quite heterogeneous and clinical characteristics
may not be reliable in predicting the underlying pathogenesis [22,23]. Many patients are misclassified as having either
type 1 or 2 diabetes.
Several different genetic abnormalities have been identified, each leading to a different type of disease. The subtypes
of MODY are defined by specific descriptions of the known genetic defects (table 2). The genes involved control
pancreatic beta cell development, function, and regulation, and the mutations in these genes cause impaired glucose
sensing and insulin secretion with minimal or no defect in insulin action [24]. Mutations in hepatocyte nuclear factor1-alpha (HNF1A) and the glucokinase (GCK) gene are most commonly identified, occurring in 52 to 65 and 15 to 32
percent of MODY cases, respectively [23,25]. Mutations in HNF4A account for approximately 10 percent of cases.
Some members of a family have the genetic defect but do not develop diabetes; the reason for this is unclear. Other
patients may have the classic MODY phenotype but do not have an identifiable mutation in any of the MODY genes
[24].
Hepatocyte nuclear factor-4-alpha Mutations in the hepatocyte nuclear factor-4-alpha (HNF4A) gene on
chromosome 20 cause the condition formerly called MODY1 [26]. HNF4A is expressed both in the liver and in
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pancreatic beta cells. One of its functions is to regulate positively the activity of HNF1A, the affected gene in the
previously labeled MODY3 syndrome. The precise mechanism by which a defect in HNF4A causes hyperglycemia is
not clear, but it has been associated with a reduced insulin secretory response to glucose, suggesting a primary
genetic defect in insulin secretion [27-29]. The secretory defect is progressive and patients typically present with
hyperglycemia in adolescence or early childhood. Although the initial response to sulfonylureas is good, patients may
require insulin as the secretory defect progresses. These patients are at risk for the microvascular and macrovascular
complications of type 1 and type 2 diabetes mellitus.
Although HNF4A plays a central role in the hepatic synthesis of lipoprotein and coagulation proteins, these functions are
largely maintained in HNF4A diabetes, suggesting that this disorder is primarily one of impaired pancreatic beta cell
function [28].
Glucokinase gene More than a dozen mutations in the glucokinase gene on chromosome 7 have been
described, and were formerly called MODY2 [30]. Defects in the expression of glucokinase, which phosphorylates
glucose to glucose-6-phosphate and probably acts as a glucose sensor, result in a higher threshold for glucose
stimulated insulin secretion. On occasion, the expressed enzyme functions but is unstable, again leading to an insulin
secretory deficit [31]. (See "Insulin secretion and pancreatic beta cell function".)
The resulting hyperglycemia is often stable, mild, and is not associated with the vascular complications that are so
common in other types of diabetes mellitus [32]. Patients with mutation in the glucokinase gene can often be controlled
with diet alone. Markers in the glucokinase locus have been linked to non-monogenic type 2 diabetes in American
blacks [33] and some other ethnic groups, but not in whites.
Hepatocyte nuclear factor-1-alpha One of several mutations in the hepatocyte nuclear factor-1-alpha (HNF1A)
gene on chromosome 12 was formerly called MODY3 [34]. This form of diabetes is more common among European
patients [35,36]. HNF1A is a weak transactivator of the insulin gene in beta cells. Mutations of HNF1A can lead to
abnormal insulin secretion; whether this or some other action is defective enough to cause diabetes mellitus is unclear
[36]. Mutations also result in a low renal threshold for glucose. Thus, prior to onset of diabetes, mutation carriers have
detectable glycosuria provoked by glucose loading [37]. Testing for glycosuria two hours after a glucose load could be
used to screen children of mutation carriers and guide the need for further evaluation.
Patients with HNF1A diabetes have a similar clinical phenotype as patients with HNF4A diabetes. Patients exhibit
increased insulin sensitivity and marked sensitivity to the hypoglycemic effects of sulfonylureas compared with
metformin (fall in FPG 85 versus 16 mg/dL [4.7 versus 0.9 mmol/L]) and compared with patients with type 2 diabetes
(3.9-fold greater reduction in FPG) [38]. Thus, patients with mutations in the HNF1A gene can be successfully treated
with sulfonylurea monotherapy, and in one clinical study, approximately 70 percent of patients previously treated with
insulin successfully switched to sulfonylureas once an HNF1A mutation was identified [39]. These patients are at risk
for microvascular and macrovascular complications of type 1 and type 2 diabetes mellitus. In addition, patients with
diabetes caused by a mutation in HNF1A appear to have an increased risk of cardiovascular mortality compared with
unaffected family members [40].
Insulin promoter factor 1 Mutations in the insulin promoter factor 1 (IPF1) gene can lead to what was called
MODY4 by reduced binding of the protein to the insulin gene promoter [41,42] and perhaps by altering fibroblast
growth factor signaling in beta cells [43]. Less severe mutations in IPF1 may predispose to late onset type 2 diabetes
[42,44]. In addition, nondiabetic carriers have higher blood glucose concentrations and lower insulin-to-glucose ratios
than nondiabetic family members without a mutation [45].
Hepatocyte nuclear factor-1-beta Mutations in the HNF1B gene produce a syndrome that was formerly called
MODY5 [46-49]. Affected patients can develop a variety of manifestations in addition to early onset diabetes. These
include pancreatic atrophy (on computed tomography [CT] scan), abnormal renal development (renal dysplasia that can
be detected on ultrasonography in the fetus, single or multiple renal cysts, glomerulocystic disease,
oligomeganephronia [a form of renal hypoplasia]), slowly progressive renal insufficiency, hypomagnesemia, elevated
serum aminotransferases, and genital abnormalities (epididymal cysts, atresia of vas deferens, and bicornuate uterus)
[47]. (See "Renal hypoplasia", section on 'Overview' and "Renal cystic diseases in children", section on 'Glomerular
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cortical cysts' and "Causes of hypomagnesemia", section on 'Hepatocyte nuclear factor-1-beta gene mutations' and
"Causes of hypomagnesemia".)
In addition, some patients have a phenotype consistent with familial juvenile hyperuricemic nephropathy [50]. (See "Uric
acid renal diseases", section on 'Familial juvenile hyperuricemic nephropathy'.)
One of the functions of HNF1B is the regulation of tissue-specific gene expression. In the kidney, the proximal promoter
of the Pkhd1 gene has a binding site for HNF1B. Mutations in HNF1B inhibit the expression of Pkhd1 and lead to cyst
formation [49]. This is not surprising since mutations in Pkhd1 are responsible for the autosomal recessive form of
polycystic kidney disease. (See "Autosomal recessive polycystic kidney disease in children", section on 'Pathogenesis'.)
Neurogenic differentiation factor-1 Mutations in the gene for neurogenic differentiation factor-1 (also called
NEUROD1 or BETA2) can lead to what was called MODY6 [51,52]. NEUROD1 normally functions as a regulatory
switch for endocrine pancreatic development.
Other genes Mutations in carboxyl ester lipase (CEL); insulin (INS); ATP-binding cassette, subfamily C, member
8 (ABCC8); potassium channel, inwardly rectifying, subfamily J, member 11 (KCNJ11); and paternal uniparental
isodisomy of chromosome 6q24 (UPD6) genes have also been associated with the MODY phenotype [24]. Mutations in
INS, ABCC8, and KCNJ11 are more commonly associated with neonatal diabetes mellitus. (See "Neonatal
hyperglycemia", section on 'Neonatal diabetes mellitus'.)
Diagnosis The diagnosis of MODY is made by performing diagnostic genetic testing by direct sequencing of the
gene. Laboratories in several countries offer clinical testing, primarily for mutations in HNF4A, HNF1A, and the
glucokinase gene. A list of laboratories is available on the GeneTests website. Only CLIA (Clinical laboratory
Improvement Amendments) certified labs should be used. Genetic testing should only be performed after informed
consent and genetic counseling. (See "Genetic counseling and testing", section on 'Practical issues in genetic testing'.)
Indications for genetic testing It is important to distinguish MODY from type 1 and type 2 diabetes because
the optimal treatment and risk for diabetes complications varies with the underlying genetic defect. As an example,
patients with MODY due to HNF1A or HNF4A mutations are frequently misdiagnosed as having insulin requiring type 1
diabetes because they present at an early age and are not obese. However, many of these patients can be
successfully managed with sulfonylureas monotherapy. In addition, distinguishing MODY from type 1 and type 2
diabetes allows earlier identification of at risk family members.
We typically perform genetic testing for MODY when there is a high index of suspicion (familial diabetes with autosomal
dominant pattern of inheritance (>2 generations), onset <25 years, non-obese, negative islet autoantibodies) (table 3)
[21,24,53].
In all patients, therefore, it is important to obtain a detailed history of diabetes at diagnosis, including age, body mass
index (BMI), and presenting symptoms [54]. It is also important to ascertain insulin dependency and the presence or
absence of family history of diabetes.
In a patient with presumed type 1 diabetes, measurement of serum autoantibodies (islet-cell antibodies [ICA], glutamic
acid decarboxylase [GAD] 65, insulin, tyrosine phosphatases, insulinoma-associated protein 2 (IA-2) and IA-2 beta)
should be performed prior to consideration of genetic testing for MODY. The presence of autoantibodies makes MODY
very unlikely [20].
It is more difficult to differentiate between MODY and type 2 diabetes mellitus. For patients with presumed type 2
diabetes, the presence of a simple (non-multigenerational) family history does not discriminate between MODY and
type 2 diabetes. Insulin resistance is not a feature of MODY. Thus, diabetes in the absence of obesity is suspicious for
MODY, particularly in adolescents with presumed type 2 diabetes. However, the absence of obesity or surrogate
markers of insulin resistance is, in general, a poor discriminator of MODY and type 2 diabetes in adults [21,54]. There
are currently no biochemical tests that reliably differentiate between the two diseases.
For family members of mutation carriers, biochemical testing to confirm diabetes should be performed before genetic
testing is considered [53]. If the biochemical tests are consistent with a diagnosis of diabetes, genetic testing can be
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performed to confirm the diagnosis of a MODY mutation. (See "Clinical presentation and diagnosis of diabetes mellitus
in adults", section on 'Diagnostic criteria'.)
Other beta cell gene defects There are other rare genetic defects in beta cell function that are not considered part
of the MODY spectrum. One type results from a dominantly inherited missense mutation in the sulfonylurea 1 receptor
subunit (SUR1) that causes hyperinsulinemia in childhood, but beta cell dysfunction and diabetes in adulthood [55,56]
(see "Pathogenesis, clinical features, and diagnosis of persistent hyperinsulinemic hypoglycemia of infancy"). Other
examples include point mutations in mitochondrial DNA [57], genetic abnormalities that result in the inability to convert
proinsulin to insulin [58], and the production of mutant insulin molecules [59].
Genetic defects in insulin action There are a series of rare abnormalities in the insulin receptor (due to a genetic
defect or the polycystic ovary syndrome) or in the structure of insulin itself. (See "Insulin resistance: Definition and
clinical spectrum".)
Genetic defects in mitochondrial DNA Maternally inherited diabetes and deafness (MIDD) is a rare mitochondrial
disorder caused by a genetic mutation at position 3243 in transfer RNA [60,61]. Although phenotypic expression is
variable, subjects universally have both a defect in insulin secretion, which progresses to insulin dependence, and
sensorineural hearing loss. The mean age of onset of diabetes and hearing loss is between the ages of 30 and 40 [61].
Other abnormalities seen include cardiac conduction defects, gestational diabetes, proteinuria, and neuropathy.
Although subjects may be treated with insulin secretagogues until insulin dependence develops, metformin is less
effective and carries a higher risk of lactic acidosis in this population [61]. Supplementation with CoQ10 may be of
some benefit. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Lactic acidosis'.)
Wolfram syndrome In addition to the specific genetic defects described above, a number of rare genetic
syndromes have been associated with diabetes. One example is the Wolfram or DIDMOAD (diabetes insipidus,
diabetes mellitus, optic atrophy, and deafness) syndrome, originally described by Wolfram in 1938 [62,63]. This
disorder is inherited as an autosomal recessive trait with incomplete penetrance.
The gene responsible for the Wolfram syndrome, named WFS1, encodes an endoplasmic reticulum membraneembedded protein called wolframin that is expressed in pancreatic beta cells and neurons [64-66]. The estimated
prevalence of Wolfram syndrome is 1 in 770,000 and it is believed to occur in 1 of 150 patients with type 1 diabetes
[66].
Affected patients usually develop insulin-requiring diabetes and optic atrophy in early childhood, and diabetes insipidus
as teenagers or young adults. The last problem is due to loss of vasopressin-secreting neurons in the supraoptic
nucleus and impaired processing of vasopressin precursors [67] (see "Clinical manifestations and causes of central
diabetes insipidus"). Anterior pituitary dysfunction has also been reported [66].
Other manifestations of Wolfram syndrome include progressive sensorineural deafness, hydronephrosis (due in part to
the high urine flow in diabetes insipidus), and neurologic dysfunction [68]. Why severe insulin-requiring diabetes
develops is not known; immunologic factors do not appear to be important [63].
DISEASES OF THE EXOCRINE PANCREAS Any disease that damages the pancreas, or removal of pancreatic
tissue, can result in diabetes. There is wide variability in the frequency with which this occurs, primarily determined by
the degree of pancreatic insufficiency (table 4) [69]. Among patients with pancreatic exocrine disease, diabetes is more
likely to occur in those with a family history of type 1 or type 2 diabetes. This observation suggests a role for an
underlying decrease in pancreatic reserve or in insulin responsiveness that makes overt diabetes more likely in patients
with pancreatic insufficiency.
Diabetes that occurs in patients with pancreatic disease is usually insulin requiring. However, it is different from typical
type 1 diabetes in that the pancreatic alpha cells, which produce glucagon, are also affected. As a result, there is an
increased risk of hypoglycemia, both treatment-related and spontaneous.
Cystic fibrosis The mechanisms of cystic fibrosis related diabetes are unique and share features with both type 1
and type 2 diabetes, with both decreased insulin production and insulin resistance [70,71]. Patients with no pancreatic
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exocrine deficiency have normal insulin secretion and responsiveness. In comparison, patients with exocrine deficiency
have decreased insulin secretion, but normal glucose tolerance due to the unusual combination of increased hepatic
glucose production and increased peripheral glucose utilization. How the latter adaptation occurs is unclear, but it is
initially able to counteract the effects of insulin deficiency. Patients with exocrine deficiency and either impaired glucose
tolerance or overt diabetes have reductions in both peripheral glucose utilization and hepatic insulin sensitivity. (See
"Cystic fibrosis: Nutritional issues", section on 'CF-related diabetes mellitus' and "Cystic fibrosis: Overview of
gastrointestinal disease", section on 'Cystic fibrosis-related diabetes (CFRD)'.)
Hereditary hemochromatosis Diabetes is common in patients with hereditary hemochromatosis, being present at
diagnosis in up to 50 percent of symptomatic patients. (See "Clinical manifestations and diagnosis of hereditary
hemochromatosis".)
Chronic pancreatitis Glucose intolerance occurs with some frequency in chronic pancreatitis, but overt diabetes
mellitus usually occurs late in the course of disease. (See "Clinical manifestations and diagnosis of chronic pancreatitis
in adults" and "Clinical manifestations and diagnosis of chronic pancreatitis in children".)
Fibrocalculous pancreatic diabetes Fibrocalculous pancreatic diabetes is a unique form of diabetes secondary to
tropical pancreatitis that is endemic in certain parts of the world (eg, southern India). In a prospective evaluation of 370
patients, all of the macrovascular and microvascular complications typically associated with diabetes were found.
Pancreatic cancer and complications of chronic pancreatitis also contribute to the mortality associated with this disease
[72]. (See "Etiology and pathogenesis of chronic pancreatitis in adults".)
Genetic linkages Both exocrine and endocrine pancreatic cells originate from the same endodermal pool. A genetic
factor common to both endocrine and exocrine pancreatic development may account for some cases of pancreatic
exocrine dysfunction with diabetes. Two Norwegian kindreds with an autosomal dominant inheritance pattern for
diabetes and exocrine pancreatic dysfunction have been identified with a single-base deletion in the carboxyl ester
lipase gene (CEL) [73]. The mechanism by which carboxyl ester lipase deficiency in pancreatic acinar cells is linked to
beta cell failure is not known [74].
ENDOCRINOPATHIES Several hormones, such as epinephrine, glucagon, cortisol, and growth hormone, antagonize
the action of insulin. Increased release of these hormones constitutes the protective counterregulatory response to
hypoglycemia. On the other hand, primary oversecretion of these hormones can result in IFG or overt diabetes. (See
"Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus".)
Endocrine abnormalities that can lead to abnormalities in glucose regulation include:
Cushing's syndrome, due to pituitary or adrenal disease or to exogenous glucocorticoid administration (see
"Epidemiology and clinical manifestations of Cushing's syndrome")
Acromegaly (see "Causes and clinical manifestations of acromegaly")
Catecholamine excess in pheochromocytoma (see "Clinical presentation and diagnosis of pheochromocytoma")
Glucagon-secreting tumors (glucagonomas), associated with an unusual constellation of other clinical features,
including skin rash, weight loss, anemia, and thromboembolic problems (see "Glucagonoma and the glucagonoma
syndrome")
Somatostatin-secreting tumors (somatostatinomas), typically associated with the triad of diabetes mellitus,
cholelithiasis, and diarrhea with steatorrhea (see "Somatostatinoma: Clinical manifestations, diagnosis, and
management")
Hyperthyroidism, which can interfere with glucose metabolism, although overt diabetes is unusual (see "Overview
of the clinical manifestations of hyperthyroidism in adults")
DRUG-INDUCED DIABETES A large number of drugs can impair glucose tolerance; they act by decreasing insulin
secretion, increasing hepatic glucose production, or causing resistance to the action of insulin (table 5). (See
"Pathogenesis of type 2 diabetes mellitus", section on 'Drug-induced hyperglycemia'.)
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VIRAL INFECTIONS Certain viruses can cause diabetes, either through direct beta cell destruction or,
hypothetically, by inducing autoimmune damage (see "Pathogenesis of type 1 diabetes mellitus"). Chronic hepatitis C
virus infection has been associated with an increased incidence of diabetes, but it is uncertain if there is a causeand-effect relationship. (See "Extrahepatic manifestations of hepatitis C virus infection", section on 'Diabetes mellitus'.)
GESTATIONAL DIABETES MELLITUS Gestational diabetes occurs when a woman's pancreatic function is not
sufficient to overcome both the insulin resistance created by the anti-insulin hormones secreted by the placenta during
pregnancy (eg, estrogen, prolactin, human chorionic somatomammotropin, cortisol, and progesterone) and the
increased fuel consumption necessary to provide for the growing mother and fetus. It is estimated to occur in
approximately 2.1 percent of pregnant women in the United States, usually developing in the second or third trimester.
(See "Diabetes mellitus in pregnancy: Screening and diagnosis".)
UNCOMMON IMMUNE-MEDIATED DIABETES Several uncommon forms of immune-mediated diabetes have been
identified.
Stiff-person syndrome The stiff-person syndrome (formerly called stiff-man syndrome) is an autoimmune disorder
of the central nervous system, which is characterized by progressive muscle stiffness, rigidity, and spasm involving the
axial muscles, with severe impairment of ambulation. Patients usually have high titers of anti-glutamic acid
decarboxylase (GAD) antibodies, and diabetes occurs in approximately one-third of cases. (See "Stiff-person
syndrome".)
Anti-insulin receptor antibodies Anti-insulin receptor antibodies can bind to insulin receptors and either act as an
agonist, leading to hypoglycemia, or block the binding of insulin and cause diabetes [75].
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best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade
reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info
and the keyword(s) of interest.)
Basics topics (see "Patient information: Type 1 diabetes (The Basics)" and "Patient information: Type 2 diabetes
(The Basics)")
Beyond the Basics topics (see "Patient information: Diabetes mellitus type 1: Overview (Beyond the Basics)" and
"Patient information: Diabetes mellitus type 2: Overview (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Type 1 diabetes is characterized by destruction of the pancreatic beta cells, leading to absolute insulin deficiency.
This is usually due to autoimmune destruction of the pancreatic beta cells. (See 'Type 1 diabetes' above.)
Type 2 diabetes is by far the most common type of diabetes, and is characterized by variable degrees of insulin
deficiency and resistance. (See 'Type 2 diabetes' above.)
It is occasionally difficult to distinguish between type 1 and atypical presentations of type 2 diabetes. We often
measure two to three autoantibodies (GAD65, insulin, tyrosine phosphatases [insulinoma-associated protein 2
{IA-2} and IA-2 beta], islet cell, or ZnT8) when the diagnosis of type 1 or type 2 diabetes is uncertain by clinical
presentation (ie, thin patient with poor response to initial therapy with sulfonylureas or metformin, personal or
family history of autoimmune disease). If one or more of the antibodies is present, and especially if two or more
are positive, the patient should be presumed to have type 1 diabetes and should be treated with insulin
replacement therapy, as these patients respond poorly to diet and oral hypoglycemic drug therapy. (See
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'Distinguishing type 1 from type 2 diabetes' above.)

As the human genome is further explored, it is likely that multiple genetic anomalies at different loci will be found
that confer varying degrees of predisposition to type 1 and type 2 diabetes. Monogenic causes of type 2 diabetes
represent only a small fraction of cases and commonly inherited polymorphisms individually contribute only small
degrees of risk for, or protection from, diabetes. Most of the genetic risk for type 2 diabetes results from complex
polygenic risk factors. (See 'Genetic defects' above and "Pathogenesis of type 2 diabetes mellitus", section on
'Genetic susceptibility'.)
Maturity onset diabetes of the young (MODY) is a clinically heterogeneous disorder characterized by non-insulin
dependent diabetes diagnosed at a young age (<25 years) with autosomal dominant transmission and lack of
autoantibodies. It is classified by the underlying genetic defect (table 2). Many patients with MODY are
misclassified as having either type 1 or 2 diabetes. (See 'Maturity onset diabetes of the young' above.)
The diagnosis of MODY is made by performing diagnostic genetic testing by direct sequencing of the gene.
Laboratories in several countries offer clinical testing, primarily for mutations in HNF4A, HNF1A, and the
glucokinase gene. (See 'Diagnosis' above.)
We typically perform genetic testing for MODY when there is a high index of suspicion (familial diabetes with
autosomal dominant pattern of inheritance (>2 generations), onset <25 years, non obese, negative islet
autoantibodies) (table 3). For family members of mutation carriers, biochemical testing to confirm diabetes should
be performed before genetic testing is considered. If the biochemical tests are consistent with a diagnosis of
diabetes, genetic testing can be performed to confirm the diagnosis of a MODY mutation. (See 'Indications for
genetic testing' above.)
Diseases that damage the pancreas, or removal of pancreatic tissue, can result in diabetes. There is wide
variability in the frequency with which this occurs, primarily determined by the degree of pancreatic insufficiency
(table 4). (See 'Diseases of the exocrine pancreas' above.)
Several endocrinopathies, including Cushing's syndrome, acromegaly, and pheochromocytoma, can lead to
abnormalities in glucose regulation. (See 'Endocrinopathies' above.)
A large number of drugs can impair glucose tolerance; they act by decreasing insulin secretion, increasing hepatic
glucose production, or causing resistance to the action of insulin (table 5). (See "Pathogenesis of type 2 diabetes
mellitus", section on 'Drug-induced hyperglycemia'.)
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