As our understanding of the pathophysiology of diabetes evolves, we increasingly recognize that many patients may have a form of diabetes that does not neatly fit with a diagnosis of either type 1 or type 2 diabetes. The discovery and description of these forms of “atypical diabetes” have led to major contributions to our collective understanding of the basic biology that drives insulin secretion, insulin resistance, and islet autoimmunity. These discoveries now pave the way to a better classification of diabetes based on distinct endotypes. In this review, we highlight the key biological and clinical insights that can be gained from studying known forms of atypical diabetes. Additionally, we provide a framework for identification of patients with atypical diabetes based on their clinical, metabolic, and molecular features. Helpful clinical and genetic resources for evaluating patients suspected of having atypical diabetes are provided. Therefore, appreciating the various endotypes associated with atypical diabetes will enhance diagnostic accuracy and facilitate targeted treatment decisions.

It is now generally recognized that the binary categorization of diabetes into type 1 and type 2 is insufficient to capture the range of metabolic and clinical phenotypes, molecular mechanisms, and disease pathogenesis that lead to the final common end point of hyperglycemia. The frequency of non–type 1, non–type 2 diabetes—now referred to as “atypical diabetes”—is likely underestimated, and the proportion varies considerably (from 5% to 11%) depending on the ethnic and other characteristics of the population studied (1).

In this review, we seek to provide an overview of some of the characteristic features of well-described forms of atypical diabetes, including examples of those for which the etiological basis is known and others for which the etiological basis is not yet fully understood. Atypical diabetes is suspected in individuals who do not fit clearly into currently accepted criteria that define type 1 diabetes (T1D), type 2 diabetes (T2D), or secondary diabetes (1,2). We introduce the concept of endotypes, in which patients with diabetes can be clustered based on similar clinical or molecular/genetic mechanisms.

Below, we discuss several examples of atypical diabetes, their etiological or mechanistic bases, and their characteristic clinical features. We provide this section as a framework for approaching patients who do not fit accepted criteria of T1D or T2D—rather than as a comprehensive review of all forms of atypical diabetes (Fig. 1).

Figure 1

Conceptualization of diabetes subtypes within three axes: insulin sensitivity, insulin secretion, and islet autoimmunity. The green area represents the normal inverse relationship between insulin sensitivity and insulin secretion. As an individual develops insulin resistance, there is an eventual loss of compensatory insulin secretion. This can result in impaired fasting glucose (pink) and insulin-resistant diabetes (type 2), as shown in dark blue. Autoimmune diabetes (T1D) is featured by overall insulin sensitivity, with near-absolute loss of insulin secretion and a high degree of islet autoimmunity. Individuals with LADA also manifest islet autoimmunity but retain insulin secretory capacity and remain insulin sensitive. Conversely, those with insulin resistance syndromes and lipodystrophies tend to have a high degree of insulin resistance and secrete high levels of insulin. Individuals with many monogenic and mitochondrial forms of diabetes secrete very low levels of insulin and remain insulin sensitive, but lack evidence of islet autoimmunity. KPD, defined according to presentation with DKA, includes four subtypes, each shown in light blue. Patients with A+β+ present with similar metabolic features compared to LADA. A+β− patients metabolically resemble T1D. Aβ individuals have near-complete insulin deficiency but lack evidence for islet autoimmunity. Aβ+ patients often manifest insulin resistance with sustained insulin secretory reserve despite presentation with DKA.

Figure 1

Conceptualization of diabetes subtypes within three axes: insulin sensitivity, insulin secretion, and islet autoimmunity. The green area represents the normal inverse relationship between insulin sensitivity and insulin secretion. As an individual develops insulin resistance, there is an eventual loss of compensatory insulin secretion. This can result in impaired fasting glucose (pink) and insulin-resistant diabetes (type 2), as shown in dark blue. Autoimmune diabetes (T1D) is featured by overall insulin sensitivity, with near-absolute loss of insulin secretion and a high degree of islet autoimmunity. Individuals with LADA also manifest islet autoimmunity but retain insulin secretory capacity and remain insulin sensitive. Conversely, those with insulin resistance syndromes and lipodystrophies tend to have a high degree of insulin resistance and secrete high levels of insulin. Individuals with many monogenic and mitochondrial forms of diabetes secrete very low levels of insulin and remain insulin sensitive, but lack evidence of islet autoimmunity. KPD, defined according to presentation with DKA, includes four subtypes, each shown in light blue. Patients with A+β+ present with similar metabolic features compared to LADA. A+β− patients metabolically resemble T1D. Aβ individuals have near-complete insulin deficiency but lack evidence for islet autoimmunity. Aβ+ patients often manifest insulin resistance with sustained insulin secretory reserve despite presentation with DKA.

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Monogenic Diabetes

The term “monogenic diabetes” is typically used to describe nonsyndromic forms of diabetes with demonstration of Mendelian inheritance driven by damaging variants in a single gene. Maturity-onset diabetes of the young (MODY) and neonatal diabetes are the two most well-described forms of monogenic diabetes. Many genes responsible for these disorders are pivotal to β-cell development or function (3). Importantly, some forms of MODY have proven to be amenable to sulfonylureas, demonstrating an early opportunity for precision medicine in diabetes (4).

A strong family history of diabetes that typically follows an autosomal dominant pattern of inheritance, with multiple affected generations, is a common hallmark of monogenic diabetes. Affected relatives may be misdiagnosed with T1D or T2D (5). Distinctive presenting features for some subtypes of MODY may also provide an index of suspicion. A comprehensive review of all forms of MODY is outside of the scope of this review. However, below, we use GCK-MODY, HNF1A-MODY, and neonatal diabetes to illustrate some of the unique etiological and clinical features of monogenic forms of diabetes. Table 1 includes a review of several well-described forms of monogenic and neonatal diabetes, for which a genetic cause has been identified, defining clinical features, and microvascular complications (6).

Table 1

Genetic causes of monogenic and neonatal diabetes

Gene symbolFull gene nameGene functionClinical featuresFrequency of microvascular complications
GCK Glucokinase Glucose sensor, first rate-limiting enzyme in glucose metabolism Stable, mild fasting hyperglycemia at birth. Typically asymptomatic; diagnosis often incidental Rare 
HNF1A Hepatocyte nuclear factor 1α β-Cell transcription factor Transient neonatal hyperinsulinemic hypoglycemia in some. Progressive insulin secretory defect. OGTT frequently needed to make an early diagnosis. Renal glycosuria Common 
HNF4A Hepatocyte nuclear factor 4α β-Cell transcription factor Birth weight >800 g above normal. Transient neonatal hyperinsulinemic hypoglycemia common. Progressive insulin secretory defect Common 
HNF1B Hepatocyte nuclear factor 1β β-Cell transcription factor Intrauterine growth restriction, kidney anomalies, urogenital tract anomalies, pancreatic hypoplasia Common 
ABCC8 and KCNJ11 ABCC8, sulfonylurea receptor subunit of β-cell KATP channel; KCNJ11, potassium channel subunit of β-cell KATP channel Closure of the KATP channel leads to β-cell membrane depolarization, calcium influx, and fusion of insulin secretory granules with β-cell membrane Can present with severe diabetes in the newborn period or present similarly to HNF1A- and HNF4A-MODY Unknown 
CEL Carboxyl ester lipase Exocrine pancreas function Pancreatic atrophy and exocrine pancreatic insufficiency. Pancreatic fibrosis and lipomatosis leading to diabetes Unknown 
NEUROD1 Neurogenic differentiation factor 1 β-Cell transcription factor Overweight/obesity in some Unknown 
PDX1 Pancreas/duodenum homeobox 1 Pancreas transcription factor Pancreatic agenesis with combined pancreatic exocrine deficiency and neonatal diabetes Unknown 
INS Insulin Production of insulin or insulin action Permanent neonatal diabetes. Also, presentation similar to that of HNF1A-MODY and HNF4A-MODY Unknown 
Gene symbolFull gene nameGene functionClinical featuresFrequency of microvascular complications
GCK Glucokinase Glucose sensor, first rate-limiting enzyme in glucose metabolism Stable, mild fasting hyperglycemia at birth. Typically asymptomatic; diagnosis often incidental Rare 
HNF1A Hepatocyte nuclear factor 1α β-Cell transcription factor Transient neonatal hyperinsulinemic hypoglycemia in some. Progressive insulin secretory defect. OGTT frequently needed to make an early diagnosis. Renal glycosuria Common 
HNF4A Hepatocyte nuclear factor 4α β-Cell transcription factor Birth weight >800 g above normal. Transient neonatal hyperinsulinemic hypoglycemia common. Progressive insulin secretory defect Common 
HNF1B Hepatocyte nuclear factor 1β β-Cell transcription factor Intrauterine growth restriction, kidney anomalies, urogenital tract anomalies, pancreatic hypoplasia Common 
ABCC8 and KCNJ11 ABCC8, sulfonylurea receptor subunit of β-cell KATP channel; KCNJ11, potassium channel subunit of β-cell KATP channel Closure of the KATP channel leads to β-cell membrane depolarization, calcium influx, and fusion of insulin secretory granules with β-cell membrane Can present with severe diabetes in the newborn period or present similarly to HNF1A- and HNF4A-MODY Unknown 
CEL Carboxyl ester lipase Exocrine pancreas function Pancreatic atrophy and exocrine pancreatic insufficiency. Pancreatic fibrosis and lipomatosis leading to diabetes Unknown 
NEUROD1 Neurogenic differentiation factor 1 β-Cell transcription factor Overweight/obesity in some Unknown 
PDX1 Pancreas/duodenum homeobox 1 Pancreas transcription factor Pancreatic agenesis with combined pancreatic exocrine deficiency and neonatal diabetes Unknown 
INS Insulin Production of insulin or insulin action Permanent neonatal diabetes. Also, presentation similar to that of HNF1A-MODY and HNF4A-MODY Unknown 

GCK-MODY (MODY 2)

GCK-MODY is the most common form of MODY, with demonstration of an autosomal dominant pattern of inheritance (7). It results from heterozygous pathogenic variants in GCK, the gene encoding glucokinase. Glucokinase performs the rate-limiting step in the conversion of glucose to glucose-6-phosphate within the pancreatic β-cell. Glucose-6-phosphate then enters the tricarboxylic acid cycle, and generates ATP, which triggers a cascade resulting in insulin secretion (8). Thus, GCK serves as the “glucostat” of the β-cell, regulating insulin secretion. Heterozygous inactivating GCK mutations result in a higher set point of glucose at which insulin is secreted (9).

Clinically, GCK-MODY presents as mild hyperglycemia in an individual lacking common metabolic risk factors for T2D (9). Patients often have a history of hemoglobin A1c (HbA1c) levels that oscillate between prediabetes and mild diabetes levels. Importantly, patients with GCK-MODY are not at increased risk for micro- or macrovascular complications of hyperglycemia (10) and thus do not require pharmacotherapy. Rather, treatment of their diabetes is often frustrating to patients as it results in either no improvement in their blood glucose or significant hypoglycemia (11). Accurate diagnosis of this condition prevents unnecessary treatment, as microvascular complications of GCK-MODY–related diabetes are exceedingly rare (6).

HNF1A-MODY (MODY 3)

The second most common form of MODY is HNF1A-MODY. With HNF1A-MODY there is also demonstration of an autosomal dominant pattern of inheritance, and HNF1A-MODY results from heterozygous pathogenic variants in hepatocyte nuclear factor 1α (HNF1A) (12). HNF1A is an important β-cell transcription factor; thus, patients with HNF1A-MODY often develop insulin-deficient diabetes in the second to third decade of life (3). Microvascular complications of hyperglycemia are common in individuals with HNF1A-MODY without appropriate treatment (6).

Importantly, HNF1A-MODY is often successfully treated with sulfonylureas, particularly if recognized early in the course of disease (13). Often, recognition of one family member with HNF1A-MODY can inform cascade testing in family members, with substantial therapeutic impact.

Neonatal Diabetes

Most commonly, neonatal diabetes is caused by loss-of-function variants in the KATP channel, composed of two subunits encoded by KCNJ11 (Kir6.2) and ABCC8 (SUR1) (14). Neonatal diabetes is typically diagnosed in the first 6 months of life, and where neonatal diabetes is not recognized early, infants may present with severe hyperglycemia and ketoacidosis (14). The severity and course of neonatal diabetes are quite variable, with some experiencing only transient metabolic dysregulation and others a more permanent form of diabetes. The most severe form of neonatal diabetes, which occurs in <1 in 1 million live births, is characterized by developmental Delay, Epilepsy, and Neonatal Diabetes (DEND). DEND typically will occur in the setting of KCNJ11 or ABCC8 mutations (15).

Oligogenic Forms of Diabetes

Initially the field of genetics and diabetes focused on highly penetrant, inherited forms of diabetes that resulted from mutations in a single gene (monogenic diabetes). However, with the explosion of genomic data becoming available over the last several years, attention is increasingly directed toward conditions in which two (digenic) or a few (oligogenic) genes with variant alleles contribute to an inherited form of diabetes. Often, these genes cluster in shared pathways, compounding the effect of multiple genes that individually would not result in significant disease (16). Examples include a case of digenic MODY with variants in HNF1A and HNF1B (17) or severe insulin resistance due to heterozygous variants in the PPARG and PPP1R3A genes (18). In other cases, additional genetic variation can explain variable or incomplete penetrance of the diabetes phenotype (19). Aided by recent advances in DNA-sequencing technology, increased ascertainment and deeper understanding of digenic and oligogenic models of atypical diabetes will continue to move the field of precision diabetes forward. Additionally, the field of genetics and diabetes has made significant progress in determining the polygenic (tens to hundreds of genes) risk for both T1D and T2D; however, this is outside of the scope of this review (20).

Syndromic Diabetes

Patients with syndromic forms of diabetes typically present with a range of atypical clinical features in addition to hyperglycemia. Unique combinations of syndromic features may arise from a single molecular defect and can provide a rationale for evaluation by an expert in medical genetics. As with monogenic diabetes, a positive family history may suggest a genetic etiology, although more severe conditions may result from de novo mutational events, thus appearing to be sporadic rather than familial. Similar to MODY, the genes responsible for syndromic forms of diabetes often encode proteins important for β-cell development, function, or survival. However, their expression in other tissues can lead to multiorgan involvement, with common examples including neurological involvement (microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome, IER31P1 variants [21]), other endocrine features (neonatal diabetes mellitus with congenital hypothyroidism syndrome, GLIS3 variants [22]), skeletal involvement (Wolcott-Rallison syndrome, EIF2AK3 variants [21]), gastrointestinal involvement (Mitchell-Riley syndrome, RFX6 variants [23]), or immunological involvement (immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome, FOXP3 variants [24]). Below, we detail the characteristic features of Wolfram syndrome as one well-studied example of syndromic diabetes.

Wolfram Syndrome

Wolfram syndrome, also known as diabetes insipidus, diabetes mellitus, optic atrophy, deafness syndrome (DIDMOAD) (25), is caused by biallelic pathogenic variants in WFS1 or CISD2 and segregates in families in an autosomal recessive pattern. WFS1 encodes wolframin, a transmembrane protein in the endoplasmic reticulum. Aberrant wolframin function leads to endoplasmic reticulum stress and dysregulation of the unfolded protein response on which mature insulin synthesis relies. As such, Wolfram syndrome is considered one of the prototypical endoplasmic reticulum stress disorders (21).

Patients with classic Wolfram syndrome often present before 16 years of age with antibody-negative, insulin-deficient diabetes. They soon develop optic atrophy and can have additional features of sensorineural hearing impairment, diabetes insipidus, urinary tract abnormalities, progressive neurodegeneration, and psychiatric disorders (25,26). Individuals with Wolfram syndrome due to CISD2 variants tend to be more severely affected and may additionally develop gastrointestinal bleeding (27).

Mitochondrial Diabetes

Subtypes of mitochondrial diabetes result from mitochondrial dysfunction. The presenting features of mitochondrial disorders can be variable, with organ systems such as the pancreas (particularly β-cells) that require high levels of aerobic metabolism the most likely to be affected. A positive family history is often observed, manifesting as a strictly maternal inheritance pattern in conditions that are caused by variants encoded in the mitochondrial genome or as autosomal recessive inheritance in conditions caused by variants encoded in the nuclear genome. Proper diagnosis of mitochondrial forms of diabetes is paramount, as treatment with metformin, often a first-line medication for T2D, is contraindicated in mitochondrial diabetes due to the increased risk of provoking lactic acidosis (28).

Clinically, mitochondrial disorders display tremendous clinical and prognostic heterogeneity which is driven in part by the identity of the etiologic variant, its degree of heteroplasmy or homoplasmy (the fraction of mitochondrial genomes in which the variant is present) if encoded in the mitochondrial genome, and cell-to-cell and tissue-to-tissue heterogeneity that is observed in these conditions. The heteroplasmic mitochondrial genome variant c.3243A>G MT-TL1 illustrates some of this complexity: individuals with this variant may develop maternally inherited diabetes-deafness syndrome (MIDD), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), Leigh syndrome, or a combination of other features observed in individuals with mitochondrial dysfunction. Diabetes, when it develops, may respond well to sulfonylureas or may be characterized by insulinopenia. Age of onset can range from early childhood to ≥40 years of age, although up to 9% of individuals will remain unaffected (29).

Lipodystrophic Forms of Diabetes

Lipodystrophic forms of diabetes are clinically characterized by loss of body fat, which may be generalized or involve limited areas of the body (“partial lipodystrophy”). Accompanying clinical characteristics include prominent musculature, phlebomegaly, severe hypertriglyceridemia, and profound hepatomegaly resulting from steatohepatitis (30). The hyperglycemia is driven by insulin resistance, which can manifest with severe acanthosis nigricans (30). Investigation of lipodystrophic syndromes has shed light on the key role of adipose tissue on metabolism and insulin sensitivity. One such adipokine, leptin, has multiple effects including the promotion of satiety (31). Another, adipokine, adiponectin, plays a key role in glucose regulation and fatty acid oxidation. Thus, together these hormones prevent complications of obesity and metabolic syndrome (31). Major categories of lipodystrophy (31) are summarized below and in Table 2.

Table 2

Major categories of lipodystrophies

DiseaseOnsetBody fatMetreleptin
CGL Infancy Absent FDA approved* 
FPLD Adolescence Limbs, buttocks, hips No 
Progeroid lipodystrophy Childhood Variable Research only 
AGL Childhood Absent FDA approved* 
DiseaseOnsetBody fatMetreleptin
CGL Infancy Absent FDA approved* 
FPLD Adolescence Limbs, buttocks, hips No 
Progeroid lipodystrophy Childhood Variable Research only 
AGL Childhood Absent FDA approved* 
*

Distribution limited under REMS program, a program to ensure that prescriptions are being used in accord with FDA-approved indications.

Congenital Generalized Lipodystrophy

Congenital generalized lipodystrophy (CGL) (Berardinelli-Seip syndrome) is characterized by near-complete lack of adipose tissue first diagnosed in infancy (32). Multiple autosomal recessive forms have been identified, associated with AGPAT2, BSCL2, CAV1, PTRF, PCYT1A, and PPARG (30). Treatment for diabetes includes metformin and insulin. Notably, extremely high doses of insulin are often required (31). Fibric acid derivatives and/or statins may be needed to lower severe hypertriglyceridemia (31). Metreleptin, a recombinant human leptin analog, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of CGL. Notably, metreleptin’s distribution is limited under a risk evaluation and mitigation strategy (REMS) program (31).

Familial Partial Lipodystrophy

Familial partial lipodystrophy (FPLD) is characterized by localized loss of fat in the limbs, buttocks, and hips. There is a concurrent accumulation of fat in other areas, often resulting in a cushingoid appearance (32). Unlike with CGL, patients with FPLD typically first present during adolescence (31). Most forms of FPLD are autosomal dominant and result from heterozygous variants in LMNA, PPARG, AKT2, or PLIN1 (30). However, autosomal recessive FPLD also occurs, resulting from biallelic variants in CIDEC, LIPE, or PCYT1A (30). Diabetes can be treated with metformin, thiazolidinediones, and high-dose insulin. Patients with FPLD often require aggressive management for hypertension and hyperlipidemia (31).

Progeroid Syndromes

Progeroid syndromes mimic physiological aging. This can include features of premature wrinkles, greying and loss of hair, osteoarthritis, loss of muscle mass, and increased risk of cancer and heart disease (33). These conditions can result in partial or generalized loss of body fat, and present during childhood (31). Genes implicated in progeroid lipodystrophy include LMNA, ZMPSTE24, SPRTN, WRN, BANF1, FBN1, CAV1, POLD1, and KCNJ6 (30). Many progeroid forms of lipodystrophy result in relatively mild to moderate diabetes and severe hypertriglyceridemia. Similar to other lipodystrophy syndromes, metformin, thiazolidinediones, and insulin are used in treatment (31).

Acquired Generalized Lipodystrophy

Acquired generalized lipodystrophy (AGL) (Lawrence syndrome) usually occurs before adolescence and results in progressive loss of whole-body fat (34). It is often associated with autoimmune diseases and thus is more common in females (34). Similar to CGL, AGL can be treated with metformin, sulfonylureas, thiazolidinediones, and high-dose insulin. Metreleptin is also FDA approved for the treatment of AGL under the REMS program (31).

Latent Autoimmune Diabetes

Latent autoimmune diabetes (LADA) is defined by the presence of islet autoantibodies but absence of insulin dependency for at least 6 months after initial diagnosis of diabetes in adults. Often, LADA patients are initially classified as having “T2D.” The frequency of LADA in cohorts of T2D patients varies between 5% and 13% (3542) depending on geographic location, patient demographics, the numbers of autoantibodies tested, and the sensitivity and cutoffs of the autoantibody assays. Both clinical features and genetic associations suggest that LADA represents a pathophysiologic overlap between T1D and T2D. Genome-wide association studies of European patients diagnosed with LADA compared with both control subjects without diabetes and subjects with T1D and T2D showed genetic correlations with both T1D and T2D (43). In a subsequent study investigating the genetic etiology of LADA and childhood-onset T1D, both LADA and T1D were associated with MHC class II. However, only T1D was associated with MHC class I. These findings support the possibility that LADA and childhood-onset T1D indeed have distinct genetic bases (44). Endotypic heterogeneity in LADA could influence the natural history of β-cell dysfunction as well as treatment approaches in these patients (41). LADA is likely underdiagnosed in clinical practice, since physicians infrequently measure islet autoantibodies in adult patients who do not appear to require insulin therapy at the time of diagnosis. Widespread autoantibody testing in patients (especially nonobese patients) with “T2D” could improve the diagnostic yield, but this conclusion must be tempered with the understanding that true “positivity” in autoantibody assays may depend on the assays used, variable titers for determining cutoffs, the transient nature of some autoantibodies at lower titer, and ethnicity (38,4549).

Ketosis-Prone Diabetes

The defining characteristic of ketosis-prone diabetes (KPD) is diabetic ketoacidosis (DKA) at presentation, in the absence of characteristic features of autoimmune T1D (50). Strikingly, this class of atypical diabetes is both clinically and etiologically heterogeneous. Four distinct subtypes of KPD have been defined based on quantitative measurements of antibody positivity (A+) or negativity (A−) and presence (β+) or absence (β−) of β-cell functional reserve (51). Within this classification, A+β− KPD most closely aligns with features of traditional, autoimmune T1D. A−β− KPD also resembles T1D, but does not have detectable islet autoantibodies. Additionally, A−β− KPD harbors a lower frequency of T1D-associated HLA susceptibility alleles (51,52), and demonstrates a lower T1D genetic risk score (53). Importantly, many patients with A−β− KPD either harbor pathogenic variants in essential β-cell transcription factors or demonstrate occult (T cell–mediated) islet autoimmunity (54,55). Individuals with A+β+ KPD are older and overweight at initial presentation with DKA and tend to have GAD65 autoantibodies with DPD epitope specificity (56) (which is associated with a milder form of islet autoimmunity) and to possess HLA alleles that are protective against islet autoimmunity (52). Patients with A−β+ KPD, specifically the subset termed “unprovoked” A−β+ KPD, superficially resemble patients with T2D but present with DKA despite adequate β-cell functional reserve (57). These patients are able to discontinue insulin therapy within 1–2 months after the initial index episode of DKA and may remain off insulin for several years, maintaining excellent glycemic control on oral therapy alone (57). Some patients with A−β+ KPD display hypercatabolism of the branched chain amino acid leucine, that explains in part their proclivity to developing ketoacidosis (58). Others have a defect in intracellular availability of arginine during periods of hyperglycemia, which severely blunts insulin secretory capacity during hyperglycemic crises (58). Studies in West African patients have suggested a role for herpesvirus 8 infection (59), and a report from Japan implicates insulin peptide–specific interferon-γ responses in the pathogenesis of KPD (60). The Aβ classification scheme for KPD has high accuracy in predicting glycemic control and insulin dependence among the different phenotypes of patients presenting with DKA, and pathophysiologic studies based on comparison of the different phenotypic subtypes have demonstrated its value as an endotypic classification (61).

Fulminant Diabetes

Fulminant diabetes has been described predominantly in patients living in Far Eastern countries. It is characterized by very sudden onset, with patients presenting usually with DKA but with normal or near-normal HbA1c at diagnosis. Although fulminant diabetes is reported frequently as a subtype of T1D, the patients often lack the typical T1D-associated islet autoantibodies, and the HLA alleles and haplotypes associated with fulminant diabetes are different from those associated with typical autoimmune T1D. Unlike LADA, patients experience a rapid destruction of β-cells within weeks. This results in a discrepancy between their current blood glucose state and their HbA1c (62).

Severe Insulin Resistance Syndromes

The etiology of many severe insulin resistance syndromes is not yet fully understood. However, early steps toward elucidation of critical mechanisms underlying disease pathogenesis have been made. Individuals with disorders of severe insulin resistance display features of hyperinsulinemia, such as severe acanthosis nigricans, and differ from those with lipodystrophy syndromes in that they do not manifest adipose tissue loss (63). Additional features may include hirsutism, polycystic ovary syndrome, impaired growth, and irregular menses. They often require substantial amounts of exogenous insulin to approach glucose homeostasis, and in some cases, hyperglycemia may be preceded by a period of hypoglycemia.

Abnormal function of the insulin signaling pathway drives a subset of severe insulin resistance syndromes, with loss-of-function variants in the gene encoding the insulin receptor (INSR). Notably, complete loss-of-function variants in INSR lead to an earlier-onset and more severe presentation of insulin resistance (Donohue syndrome) than with partial loss-of-function variants (Rabson-Mendenhall syndrome), providing a functional rationale for the molecular pathogenesis.

Early evidence suggests that severe insulin resistance syndromes may be amenable to precision therapeutics. For example, insulin sensitizers such as metformin and pioglitazone have shown efficacy in Rabson-Mendenhall syndrome (64). Other proposed treatment strategies exploit the shared structural homology and interrelated signaling pathways of insulin and insulin-like growth factor-1 (IGF-1); e.g., recombinant IGF-1 treatment can improve glucose control and overall life span in Donohue syndrome (65).

Type A insulin resistance syndrome results from heterozygous or mild homozygous mutations in INSR. It presents later in life, and women often struggle with menometrorrhagia, ovarian cysts, and subfertility (66). Type B insulin resistance syndrome, conversely, occurs due to polyclonal antibodies against the insulin receptor. It typically presents in adulthood, primarily in middle-aged women. Patients with type B insulin resistance syndrome will experience both hypo- and hyperglycemia based on antibody-mediated activation and subsequent downregulation of the insulin receptor (66). Often, type B insulin resistance is diagnosed in the setting of other autoimmune conditions or as part of a paraneoplastic syndrome (66). Insulin autoimmune syndrome (Hirata disease) is characterized by spontaneous episodes of hypoglycemia due to the presence of high titers of insulin autoantibodies (67).

Insulin-mediated pseudoacromegaly (IMPA) is an example of severe insulin resistance characterized by accelerated rather than impaired growth. First recognized in 1993, its etiology remained elusive until exome sequencing (ES) was applied for a female proband and sister sharing features of IMPA and their unaffected parents in 2020 (68). Variant analysis revealed a maternally inherited FGFR1 variant and a paternally inherited KLB variant in both the proband and her sister. Functional studies showed that these variants combined to reduce the insulin-sensitizing impact of FGF21, supporting a digenic model of inheritance in this family and providing the first molecular etiology of IMPA (68). These findings suggest the enticing possibility that treatment with FGF21 analogs or thiazolidinediones, which induce hepatic FGF21 expression, may be efficacious in this form of atypical diabetes (69,70).

Diabetes Secondary to Pancreatic Disease

Some forms of atypical diabetes are associated with exocrine pancreatic disease, and these are typically referred to as pancreatogenic diabetes, classified by the American Diabetes Association as type 3c diabetes. This class of atypical diabetes comprises a heterogeneous group of conditions that may be inherited or acquired, including cystic fibrosis, hemochromatosis, chronic pancreatitis, fibrocalculous pancreatopathy, pancreatic cancer, pancreatectomy, and congenital pancreatic agenesis (71,72). In many cases, the pathogenesis underlying diabetes development in these conditions is incompletely understood.

Additional Forms of Atypical Diabetes

The representative forms of atypical diabetes described above do not encompass all reported forms of this heterogeneous condition. In Table 3, we provide a summary of the major forms of atypical diabetes currently known, with their key features manifested as presence or absence of insulin sensitivity, insulin secretion, and autoimmunity, as well as other distinctive clinical characteristics.

Table 3

Key characteristics of major forms of atypical diabetes

Insulin sensitivityInsulin secretionIslet autoimmunityOther features
Monogenic diabetes +/− − Variable insulin secretion depending on gene. Some are responsive to sulfonylureas 
Syndromic diabetes +/− +/− +/− Variable presentation based on specific syndrome 
Mitochondrial diabetes +/− +/− − Loss of insulin secretion and insulin resistance during crises 
Lipodystrophies −−− ++ − Generalized or localized loss of adipose tissue 
Insulin resistance syndromes −−−− +++ − Severe acanthosis nigricans 
A+β+ KPD − ++ Predilection for DPD epitope–specific GAD65Ab and protective HLA alleles 
A−β+ KPD − − Obese/overweight with unprovoked DKA, prolonged insulin-free remission 
A−β− KPD − − Novel forms of monogenic diabetes or occult (e.g., T cell) islet autoimmunity 
Pancreatogenic diabetes +/− +/− − History of pancreatitis, cystic fibrosis, hemochromatosis, or pancreatic cancer 
Fulminant diabetes +/− −− +/− Very acute onset (HbA1c often normal despite initial presentation with DKA). Labile blood glucose levels and high risk of diabetes complications 
LADA +/− +/− Often presents in older age with slower rate of β-cell loss 
Slowly progressive autoimmune diabetes Honeymoon period with partial remission of disease 
Nonobese insulin-insufficient diabetes − − Typically, BMI within “normal” or “lean” range at and prior to time of diagnosis 
Insulin sensitivityInsulin secretionIslet autoimmunityOther features
Monogenic diabetes +/− − Variable insulin secretion depending on gene. Some are responsive to sulfonylureas 
Syndromic diabetes +/− +/− +/− Variable presentation based on specific syndrome 
Mitochondrial diabetes +/− +/− − Loss of insulin secretion and insulin resistance during crises 
Lipodystrophies −−− ++ − Generalized or localized loss of adipose tissue 
Insulin resistance syndromes −−−− +++ − Severe acanthosis nigricans 
A+β+ KPD − ++ Predilection for DPD epitope–specific GAD65Ab and protective HLA alleles 
A−β+ KPD − − Obese/overweight with unprovoked DKA, prolonged insulin-free remission 
A−β− KPD − − Novel forms of monogenic diabetes or occult (e.g., T cell) islet autoimmunity 
Pancreatogenic diabetes +/− +/− − History of pancreatitis, cystic fibrosis, hemochromatosis, or pancreatic cancer 
Fulminant diabetes +/− −− +/− Very acute onset (HbA1c often normal despite initial presentation with DKA). Labile blood glucose levels and high risk of diabetes complications 
LADA +/− +/− Often presents in older age with slower rate of β-cell loss 
Slowly progressive autoimmune diabetes Honeymoon period with partial remission of disease 
Nonobese insulin-insufficient diabetes − − Typically, BMI within “normal” or “lean” range at and prior to time of diagnosis 

The number of plus (+) and minus (−) signs indicates the degree of difference.

A summary of the approach to a patient with atypical diabetes is outlined in Fig. 2.

Figure 2

Approach to the patient with atypical diabetes. Features including the aspects of the clinical disease course, family history, and physical exam, as well as informative diagnostic tools, are outlined. When clinical investigation does not yield a definitive atypical diabetes diagnosis, research options may be considered. Image created with BioRender.com.

Figure 2

Approach to the patient with atypical diabetes. Features including the aspects of the clinical disease course, family history, and physical exam, as well as informative diagnostic tools, are outlined. When clinical investigation does not yield a definitive atypical diabetes diagnosis, research options may be considered. Image created with BioRender.com.

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When to Suspect Atypical Diabetes?

As described above and in Table 3, atypical diabetes in patients can present in a multitude of ways; hence, a thorough family history is very important. For example, many forms of monogenic diabetes are transmitted in an autosomal dominant manner (73). A family history of individuals presenting with similar features along multiple generations can be an important clue that prompts the clinician to perform further testing.

The presentation and progression of a patient’s illness can be another important distinguishing feature. For example, syndromic forms of diabetes will present with manifestations in specific affected organ systems. Patients with mitochondrial diabetes often present with deafness or lactic acidosis (28). A careful medical history can point to a diagnosis of pancreatogenic, fulminant, and slowly progressive forms of diabetes. Conversely, patients with the A−β+ and A+β+ subtypes of KPD will have a striking history of initial presentation with DKA, followed by insulin-free remission within 4–6 months (74).

Physical examination must be thorough, with specific attention paid to manifestations of insulin resistance, adipose tissue disorders, and the syndromes noted above. It is paramount to diagnose lipodystrophy, as identifying areas and patterns of adipose tissue loss can inform the diagnosis (30). Patients with lipodystrophic forms of diabetes will often have extremely elevated triglyceride and low HDL cholesterol levels. Patients with insulin resistance syndromes will have characteristic physical findings including severe acanthosis nigricans and hirsutism (63).

Clinical Tests That Help Identify and Classify Forms of Atypical Diabetes

It is very helpful to measure clinically reliable markers of islet autoimmunity, β-cell function, insulin sensitivity, and genetic variants underlying known forms of monogenic diabetes in patients suspected of having atypical diabetes.

Islet Autoimmunity

The four most common autoantibodies in people with autoimmune diabetes are autoantibodies against GAD (GAD65), islet antigen 2 (IA-2), insulin, and zinc transporter 8 (ZnT8) (49). Autoantibodies against insulin may be unreliable for patients already treated with exogenous insulin (75). Autoantibody positivity may wane with time (76,77); hence, it is important to try to measure these when a patient is first diagnosed with diabetes. Identification of patients with high titers of multiple islet autoantibodies strongly suggests autoimmune form of diabetes such as T1D, LADA, or an “A+” subtype of KPD (49,55). The significance of a low titer of a single diabetes autoantibody is not clear (7880).

It is useful to measure serum insulin or C-peptide levels as a marker of the patient’s endogenous insulin secretory capacity (81). C-peptide is cleaved from proinsulin as it is processed into mature insulin and is not a component of therapeutic insulin preparations; hence, its serum level can reflect residual β-cell capacity (82). Different cutoffs of fasting C-peptide levels have been derived in different patient cohorts with varying clinical conditions for determination of whether a patient has adequate β-cell functional reserve (83,84).

For evaluation of insulin secretion in a dynamic fashion, patients can be evaluated with an oral glucose tolerance test (OGTT) (85,86). Glucose and insulin/C-peptide can be drawn at baseline and every 30 min over the course of 120 min after consumption of 75 g (or, in children, 1.75 g/kg) oral glucose solution (87). Insulin, C-peptide, and glucose data from an OGTT allow the endocrinologist to calculate a range of indices of insulin secretory capacity such as the C-peptide index (CPI): (C-peptide30min − C-peptide0min) / (glucose30min − glucose0min). CPI <0.245 is suggestive of insulin deficiency (88). Compared with an OGTT, the mixed-meal tolerance test (MMTT) generates a stronger β-cell response as incretin hormones are modulated by ingestion of glucose, protein, and fat (89,90). In the U.S., BOOST High Protein (Nestle Health Science) is commonly used as the “mixed meal,” at a dose of 6 mL/kg with a maximum dose of 360 mL in older children and adults (91). The OGTT and MMTT can also provide indirect evidence of insulin resistance if the stimulated C-peptide levels remain high throughout the 2-h test in the presence of sustained hyperglycemia (92).

When performing an OGTT or MMTT is not feasible, the insulin dose–adjusted HbA1c (IDAA1c) measurement can be a helpful surrogate. The IDAA1c is calculated as follows: HbA1c (%) + [4 × insulin dose (units/kg/24 h)]. IDAA1c ≤9 corresponds to a predicted stimulated C-peptide >0.9 ng/mL and partial recovery of β-cell function (93).

In considering a diagnosis of monogenic diabetes, online probability calculators are available to aid in clinical decision-making. By entering readily available demographic and clinical information such as age at diagnosis, BMI, insulin requirement, and HbA1c into the calculator, the clinician can obtain a value that indicates the patient’s likelihood of having monogenic diabetes (94). Such tools provide decision support to order genetic testing and to convince third-party payers to approve such testing. Some literature suggests a cutoff of 36% probability with a positive predictive value of 74.4% in using the Exeter MODY probability calculator (https://www.diabetesgenes.org/exeter-diabetes-app/ModyCalculator) (87).

In the case of pancreatic diabetes, patients may have low fecal elastase (95). For patients with insulin-resistant forms of diabetes it may important to rule out Cushing disease by measuring 24-h urine free cortisol, measuring midnight salivary cortisol, or performing a low-dose dexamethasone suppression test (96). In the case of overgrowth syndromes, such as IMPA, it is important to rule out growth hormone excess by measuring IGF-1 and growth hormone or by performing a growth hormone suppression test (97).

Ordering and Interpreting Genetic Testing

Molecular genetic testing is a powerful tool to secure a diagnosis of single-gene atypical diabetes disorders and identify relatives at risk. Until recently, there were limited clinical guidelines regarding when to consider genetic testing for atypical diabetes. The International Society for Pediatric and Adolescent Diabetes (ISPAD) now provides a framework for consideration of testing for well-defined monogenic forms of atypical diabetes, including MODY and neonatal diabetes (98). Risk calculators, such as the Exeter MODY risk calculator, can provide a more objective approach to assessment of risk and stratification of patients who are most likely to benefit from molecular testing.

Genetic testing approaches have evolved in recent years, with broad-based molecular tests (exome sequencing [ES], array comparative genomic hybridization) demonstrating an increased diagnostic utility in comparisons with targeted gene panels that require a clinician to accurately presuppose the molecular diagnosis. Despite this evolution, some unique variants are most sensitively detected by methodologies other than ES or array comparative genomic hybridization, and the choice of testing should be informed by the sensitivity and specificity of available tests for the suspected diagnosis (99). From a practical standpoint in the clinic, gene panels and focused testing remain more accessible to many patients, due to high out-of-pocket costs and in some cases limited insurance coverage of ES testing. While the implementation of next-generation sequencing methods has had a tremendous impact on clinical diagnostics in rare disease, implicit bias remains a barrier to equitable access to testing and should be recognized and minimized (100).

Results of genetic testing can be complex. Pretest counseling of patients is important to address possible results and review the risks, benefits, and potential limitations of testing. Current American College of Medical Genetics and Genomics practice guidelines recommend that diagnostic laboratories follow a standardized interpretation process to classify variants along a spectrum from “benign” to “pathogenic” to describe their functional impact (101). Within this classification scheme are variants of uncertain significance, for which there is limited evidence to support a classification of “pathogenic/likely pathogenic” or “benign/likely benign.” Variants of uncertain significance can often present a challenge to the clinical interpretation and actionability of results. Fortunately, as new information comes to light about a variant, reanalysis of the patient’s genetic data can lead to more unequivocal reclassification of the variant as benign or pathogenic.

We characterize current precision medicine approaches to atypical diabetes in Table 4. The future dream of precision diabetes is that all patients will receive a diagnosis of a specific form of diabetes based on an extensive, endotypic classification, with genome sequencing, transcriptomic, and metabolomic data available to clinicians to inform individualized management plans. Currently, such a classification does not exist and the clinical utility of such data in diabetes care is limited. The Rare and Atypical Diabetes Network (RADIANT) exemplifies this approach and research focus needed to elucidate all forms of atypical diabetes, their clinical characteristics, and their molecular and pathophysiological etiologies (2). This work will inform implementation of omics tools for diagnostic and therapeutic purposes and enable a more complete cataloging and classification of atypical diabetes. Such advances informing diabetes care at an individualized level will be truly transformative when achieved at scale, and current research in atypical diabetes is positioned to establish new standards for the implementation of multiomics in routine clinical care.

Table 4

Precision approaches to atypical diabetes

CategoryDiseaseTreatmentNotes
Monogenic diabetes GCK-MODY Not necessary Low risk of microvascular complications 
 HNF1A-MODY SU, GLP-1 RA, SGLT-2i, insulin Low renal glucose threshold 
 HNF4A-MODY SU, insulin Low levels of apolipoprotein and triglycerides, neonatal macrosomia, neonatal hypoglycemia 
 HNF1B-MODY SU, insulin Genitourinary abnormalities 
 Other MODYs Likely require insulin  
Neonatal diabetes ABCC8 May respond to SU, insulin Monitor for developmental delays and/epilepsy (DEND syndrome) 
 KCNJ11 May respond to SU, insulin Monitor for developmental delays and/epilepsy (DEND syndrome) 
Syndromic diabetes MEDS Insulin Microcephaly with simplified gyral pattern, epilepsy, neonatal diabetes 
 NDH Insulin Neonatal diabetes with congenital hypothyroidism 
 Wolcott-Rallison syndrome Insulin Severe skeletal abnormalities 
 Mitchell-Riley syndrome Insulin Severe gastrointestinal abnormalities 
 IPEX syndrome Insulin Immune dysregulation, polyendocrinopathy, enteropathy, X-linked 
 Wolfram syndrome Insulin Diabetes insipidus, optic atrophy, deafness 
Mitochondrial diabetes MIDD Insulin Metformin is contraindicated due to increased risk of lactic acidosis 
 MELAS Insulin  
 Leigh syndrome Insulin  
Lipodystrophy syndromes CGL Metreleptin, metformin, SU, TZDs, insulin May require very-high-dose insulin (U-500), severe TG elevation 
 FPLD Metformin, TZDs, insulin May require very-high-dose insulin (U-500), severe TG elevation, severe HTN 
 Progeroid lipodystrophy Metformin, TZDs, insulin Progeroid clinical features 
 AGL Metreleptin, metformin, SU, TZDs, insulin May require very-high-dose insulin (U-500) 
KPD A+β+ Metformin, insulin when needed Older, overweight 
 A−β+ Metformin, insulin when needed Longer-term insulin independence 
 A−β− Insulin, may benefit from metformin May have occult autoimmunity 
LADA  Insulin Often fail noninsulin therapies 
Fulminant diabetes  Insulin Rapid β-cell destruction, hyperglycemia out of proportion to HbA1c 
Severe insulin resistance syndromes Donohue syndrome IGF-1 Growth restriction 
 Rabson-Mendenhall syndrome Metformin, TZDs, IGF-1 Severe acanthosis nigricans 
 Type A insulin resistance syndrome Metformin, TZDs, GLP-1 RA, insulin Severe PCOS, may require high doses of insulin 
 Type B insulin resistance syndrome Corticosteroids, metformin, hydroxychloroquine, methotrexate Paraneoplastic syndrome of connective tissue disease 
 Insulin autoimmune syndrome Supportive therapy, somatostatin analogs, diazoxide, glucocorticoids, azathioprine, rituximab Triggered by drugs or viruses or spontaneous 
Pancreatic diabetes (type 3C)  Insulin Manage pancreatic exocrine deficiency 
CategoryDiseaseTreatmentNotes
Monogenic diabetes GCK-MODY Not necessary Low risk of microvascular complications 
 HNF1A-MODY SU, GLP-1 RA, SGLT-2i, insulin Low renal glucose threshold 
 HNF4A-MODY SU, insulin Low levels of apolipoprotein and triglycerides, neonatal macrosomia, neonatal hypoglycemia 
 HNF1B-MODY SU, insulin Genitourinary abnormalities 
 Other MODYs Likely require insulin  
Neonatal diabetes ABCC8 May respond to SU, insulin Monitor for developmental delays and/epilepsy (DEND syndrome) 
 KCNJ11 May respond to SU, insulin Monitor for developmental delays and/epilepsy (DEND syndrome) 
Syndromic diabetes MEDS Insulin Microcephaly with simplified gyral pattern, epilepsy, neonatal diabetes 
 NDH Insulin Neonatal diabetes with congenital hypothyroidism 
 Wolcott-Rallison syndrome Insulin Severe skeletal abnormalities 
 Mitchell-Riley syndrome Insulin Severe gastrointestinal abnormalities 
 IPEX syndrome Insulin Immune dysregulation, polyendocrinopathy, enteropathy, X-linked 
 Wolfram syndrome Insulin Diabetes insipidus, optic atrophy, deafness 
Mitochondrial diabetes MIDD Insulin Metformin is contraindicated due to increased risk of lactic acidosis 
 MELAS Insulin  
 Leigh syndrome Insulin  
Lipodystrophy syndromes CGL Metreleptin, metformin, SU, TZDs, insulin May require very-high-dose insulin (U-500), severe TG elevation 
 FPLD Metformin, TZDs, insulin May require very-high-dose insulin (U-500), severe TG elevation, severe HTN 
 Progeroid lipodystrophy Metformin, TZDs, insulin Progeroid clinical features 
 AGL Metreleptin, metformin, SU, TZDs, insulin May require very-high-dose insulin (U-500) 
KPD A+β+ Metformin, insulin when needed Older, overweight 
 A−β+ Metformin, insulin when needed Longer-term insulin independence 
 A−β− Insulin, may benefit from metformin May have occult autoimmunity 
LADA  Insulin Often fail noninsulin therapies 
Fulminant diabetes  Insulin Rapid β-cell destruction, hyperglycemia out of proportion to HbA1c 
Severe insulin resistance syndromes Donohue syndrome IGF-1 Growth restriction 
 Rabson-Mendenhall syndrome Metformin, TZDs, IGF-1 Severe acanthosis nigricans 
 Type A insulin resistance syndrome Metformin, TZDs, GLP-1 RA, insulin Severe PCOS, may require high doses of insulin 
 Type B insulin resistance syndrome Corticosteroids, metformin, hydroxychloroquine, methotrexate Paraneoplastic syndrome of connective tissue disease 
 Insulin autoimmune syndrome Supportive therapy, somatostatin analogs, diazoxide, glucocorticoids, azathioprine, rituximab Triggered by drugs or viruses or spontaneous 
Pancreatic diabetes (type 3C)  Insulin Manage pancreatic exocrine deficiency 

SU, sulfonylureas; GLP-1 RA, glucagon-like peptide 1 receptor agonists; HTN, hypertension; IPEX syndrome, immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome; MEDS, microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome; NDH, neonatal diabetes mellitus with congenital hypothyroidism; PCOS, polycystic ovary syndrome; SGLT-2i, sodium–glucose cotransporter 2 inhibitors; TG, triglycerides; TZDs, thiazolidinediones.

This article is featured in podcasts available at diabetesjournals.org/care/pages/diabetes_care_on_air.

Note Added in Proof. Between initial publication of this article online and its final publication online and in print, the genes KLF11, PAX4, and BLK were removed from Table 1 due to a recent refutation of their roles in monogenic diabetes. In addition, the print and initial online versions incorrectly stated that patients with pancreatic diabetes may have elevated fecal elastase; this has been corrected to reflect that patients with pancreatic diabetes may have low fecal elastase.

Acknowledgments. J.E.P. is an editor of Diabetes Care but was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Funding. S.I.S. is supported by a K08 grant from the National Institutes of Health (NIH) (DK124574). The authors are also supported by the RADIANT study, funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Duality of Interest. No potential conflicts of interest relevant to this article were reported.

Author Contributions. S.I.S. researched and authored sections pertaining to monogenic, syndromic, mitochondrial, severe insulin resistance lipodystrophic, and pancreatic diabetes. S.I.S. also researched and authored the section on the approach to the patient with atypical diabetes. A.B. researched and authored sections on LADA, KPD, and fulminant diabetes. J.E.P. researched and authored sections on defining atypical diabetes, ordering and interpreting genetic testing, and atypical diabetes and precision medicine. All authors reviewed and edited the manuscript in its entirety.

Handling Editors. The journal editors responsible for overseeing the review of the manuscript were Steven E. Kahn and Adrian Vella.

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