Overview of Atypical Diabetes

INTRODUCTION

Although a majority of children and adults with diabetes mellitus (DM) are diagnosed with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D), a significant number of patients with DM do not meet T1D or T2D diagnostic criteria or have atypical manifestations of their DM.¹ Monogenic diabetes is estimated to comprise up to 6.5% of the pediatric diabetes population,^1,2 mostly among those classified as T1D but without evidence of pancreatic islet autoimmunity. In 1 study, however, 8% of patients clinically diagnosed with T2D carry mutations in genes associated with monogenic diabetes.³ Other rare forms of diabetes related to mitochondrial defects, severe insulin resistance syndromes, and lipodystrophy also contribute to the population of patients with atypical forms of diabetes.⁴ Collectively, patients who do not have clear presentations of either T1D or T2D may represent a unique population enriched in both known and as yet undefined monogenic causes of diabetes.

Diagnostic criteria set by the American Diabetes Association remain the same for all forms of DM: hemoglobin (Hb)A_1C greater than or equal to 6.5%, fasting blood glucose greater than or equal to 126 mg/dL, oral glucose tolerance test (OGTT) 2-hour glucose greater than or equal to 200 mg/dL, or a random glucose greater than or equal to 200 mg/dL in a patient with classic symptoms of hyperglycemia.⁵ Special consideration is needed, however, to select appropriate testing to establish the etiology when atypical diabetes is suspected.

The objective of this article is to provide a brief overview of subtypes, mechanisms, diagnostic considerations, and management approaches in the various forms of atypical diabetes. Fig. 1 provides an algorithm for considerations in testing for atypical forms of diabetes.

Fig. 1.

Diagnostic algorithm for atypical diabetes. GU, genitourinary; Hx, History.

MONOGENIC DIABETES

Monogenic diabetes, including maturity-onset diabetes of the young (MODY) and neonatal DM (NDM), refers to diabetes caused by a single gene mutation.

Neonatal Diabetes Mellitus

NDM, a rare disorder, with incidence of 1 in 90,000 to 1 in 400,000,^6,7 is characterized by onset of persistent hyperglycemia within the first 6 months to 12 months of life.⁸ NDM arises from a single-gene mutation that affects pancreatic β-cell development and function.⁹ Approximately 25% of cases are transient and resolve by ages 6 months to 18 months, whereas 75% are permanent.⁹

Transient neonatal diabetes mellitus

A majority of transient NDM (TNDM) cases are due to an activating heterozygous mutation in a gene encoding a subunit of the pancreatic β-cell K_ATP channel (KCNJ11 and ABCC8) or linked to genetic or epigenetic changes at chromosome 6q24. In 6q24 TNDM, hyperglycemia often is followed by a hypoglycemic phase with hyperglycemia re-presenting in adulthood in approximately 50% of individuals.¹⁰

Permanent neonatal diabetes mellitus

More than 20 mutations, both dominant and recessive, have been reported to cause permanent NDM (PNDM) by altering β-cell function, causing β-cell destruction, or disrupting normal pancreatic development. These mutations result in decreased insulin production and/or secretion and may have associated syndromic comorbidities (Table 1). Dominant mutations in KCNJ11 and ABCC8 account for approximately 50% of PNDM cases. Although mutations involving the K_ATP channel subunits most commonly present with congenital hyperinsulinism or PNDM, mutations in ABCC8 and KCNJ11 also can present with diabetes later in life.

Table 1.

Overview of causes of monogenic diabetes

MODY Type/Syndrome	Gene	Protein Encoded by Gene	Percent	Associated Manifestations	Specific Treatments (If Applicable)
Neonatal Diabetes			Neonatal Diabetes Mellitus, Noncon-sanguineous (%)9
Altered β-cell functiona
MODY 12	ABCC816	KATP outer subunit SUR1	17%	Developmental delay, epilepsy9	Sulfonylureas
DEND MODY 13	KCNJ1117	KATP inner subunit Kir6.2	28.9%	Developmental delay and epilepsy (only in severe cases)	Sulfonylureas ± insulin
MODY 10	INS18	Preproinsulin	10.8%	Typically cause NDM but can lead to DM in older children/adults18	Insulin
Fanconi-Bickel syndrome	SCL2A2 (GLUT2)	—	0.3%	Hepatic dysfunction Hypergalactosemia Hypoglycemia	—
Rogers syndrome	SLC19A219	—	0.3%	Megaloblastic anemia Sensorineural hearing loss	Thiamine
β-cell destructionb,c
Wolcott-Rallison syndrome	EIFAK322	Translation initiation factor 2-alpha kinase 3	2.5% (24.3% consanguineous)	Hepatic dysfunction Skeletal dysplasia	Insulin
IPEX	FOXP323	Transcription factor	1.4%	Immune dysregulation Polyendocrinopathy Enteropathy	Insulin
MODY			Percent of all MODY35
MODY 1	HNF4A	Transcription factor	5%36	Diazoxide responsive hyperinsulinism Renal Fanconi syndrome Liver dysfunction37	Sulfonyurea15
MODY 2	GCK	Glucokinase	20–50%36		None15
MODY 3	HNF1A	Transcription factor	20–50%36	Diazoxide responsive hyperinsulinism37	Sulfonyureas15
MODY 4	PDX1	Transcription factor	1%	Pancreatic agenesis (NDM) Pancreatic exocrine deficiency38	Insulin
MODY 5	HNF1B	Transcription factor	<1%	Renal disease (cysts) Abnormal liver function Hyperuricemia and gout Pancreatic exocrine deficiency Autism spectrum disorder Genital tract anomalies Hypomagnesemia39,40 Hyperparathyroidism	Insulin
MODY 6	NEUROD1	Transcription factor	<1%	Cerebellar hypoplasia Vision deficits Sensorineural hearing loss Learning difficulties32	Insulin
MODY 7	KLF1141	Transcription factor	<1%	Present very similarly to “typical” T2D42	—
MODY 8	Carboxyl ester lipase		<1%	Defect in bile salt-dependent responsive lipase Pancreatic exocrine deficiency43	—
MODY 9	PAX4	Transcription factor	<1%	Ketosis-prone DM44 Identified in groups of patients from West Africa
MODY 11	BLK45	Tyrosine kinase	<1%	—	—
MODY 14	APPL1	Involved in insulin signaling46	<1%	—	—
Pigmented hypertrichotic dermatosis with insulin-dependent DM	SLC29A342	Nucleoside transport hENT3p		Pigmented hypertrichosis Cardiomyopathy Severe chronic inflammation47	Insulin

^aOther mutations leading to altered ß-cell function: GCK²⁰, RFX6²¹

^bOther mutations leading to ß-cell destruction: INS, IER3IPI²⁴.

^cMutations leading to abnormalities in pancreatic development include: PDX1/IPF1,²⁵ PTF1A (associated with cerebellar agenesis),²⁶ HNF1B,²⁷ RFX6,²¹ GATA4,²⁸ GATA6,²⁹ GLIS3 (associated with hypothyroidism),³⁰ NEUROG3,³¹ NEUROD1,³² PAX6 (associated with eye anomalies),³³ NKX2-2,³⁴ MNX1³⁴

Abbreviations: DEND, Developmental delay, epilepsy, and neonatal diabetes syndrome; IPEX, Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Data from Refs.^9,15–47

Diagnostic considerations

Patients with NDM may have a history of intrauterine growth restriction or low birth weight due to insulin deficiency in utero.¹¹ Similar to children with other forms of diabetes, infants often present with polyuria and poor weight gain. Affected infants are at high risk of diabetic ketoacidosis (DKA) at diagnosis, but symptoms (polyuria, tachypnea, irritability, lethargy, and hypovolemia) often are nonspecific and difficult to recognize.¹² Infants with PNMD due to pancreatic aplasia or hypoplasia may present with malabsorptive diarrhea due to pancreatic exocrine insufficiency.¹³

Diagnostic work-up of the neonate with hyperglycemia should include evaluation for alternative etiologies, including sepsis, high glucose infusion rate in parenteral nutrition, or medications (eg, corticosteroids and β-adrenergic agonists). Insulin secretory capacity should be evaluated through measurement of C peptide and insulin, and ketoacidosis should be assessed. HbA_1C greater than 6.5% is consistent with a diagnosis of DM, but normal HbA_1C in this population is not reassuring and reflects high percent of fetal hemoglobin. Islet cell autoantibodies (insulin, IA-2, GAD65, and Znt8) should be measured to exclude T1D in patients age greater than 6 months. Abdominal ultrasound can assess for pancreatic agenesis, and fecal elastase can evaluate for pancreatic exocrine deficiency.

Genetic diagnosis may focus treatment options, enable counseling regarding associated manifestations, and provide insight regarding the likelihood of permanency. Clinically significant hyperglycemia requires treatment with insulin. Given that a majority of NDM mutations (KCNJ11 and ABCC8) respond to sulfonylureas, however, empiric trial of sulfonylurea therapy under the direction of a pediatric endocrinologist while awaiting genetic testing may be considered.¹⁴

Maturity-Onset Diabetes of the Young

MODY includes forms of DM that are caused by a single-gene mutation presenting after infancy. Many, but not all, genes linked to MODY also are associated with NDM. Significant variability in the presentation and treatment exists (see Table 3). Fig. 1 provides an algorithm for specific features that may prompt MODY evaluation. Fig. 2 provides a schematic of the mechanisms of monogenic diabetes.

Table 3.

Overview of antidiabetic medications in mitochondrial diseases and monogenic diabetes

Treatment	Examples105, 114	Possible Benefits	Risks to Consider in Mitochondrial Diabetes and Monogenic Diabetes
Insulin		Necessary for use in those with minimal insulin secretion95	Hypoglycemia Risk factors for hypoglycemia (deficits in gluconeogenesis, growth deficiency, and adrenal insufficiency).63,115 Decreases seizure threshold in those with seizures116 Dose adjustments needed in chronic kidney disease117 Weight gain118 Special considerations due to impairment in dexterity or vision (insulin injection aids or pens recommended)119 Possible increased risk for insulin edema120
Biguanides	Metformin	Frequently used and long-term data in other populations	Gastrointestinal side effects Risk of lactic acidosis Reports of use in MIDD and FA Risk of lactic acidosis is a concern (although no reported cases in MIDD)67,68,79,95 Risk of vitamin B12 deficiency/neuropathy121 Inhibits complex I Not clear if this affects use in mitochondrial DM122 Discontinue in chronic kidney disease stages 3b–5123
Sulfonylureas	Glipizide Glyburide Glimepiride Chlorpropamide Tolbutamide	Frequently used and long-term data in other populations Prior to the development of other agents, has historically been a first option95 Depolarizes β-cell membrane to stimulate insulin secretion (KCNJ11 and ABCC8 mutations)14	Hypoglycemia (start on low dose using medicine with short half-life)53 Discontinue in chronic kidney disease stages 4–5123 MODY: may require higher doses One algorithm: initial twice-daily dose of 0.1 mg/kg of glyburide with escalation up to 1 mg/kg/d within 5–6 d14 HNF1A and HNF4A may respond to sulfonylurea at lower doses
Thiazolidinediones	Pioglitazone Rosiglitazone	Possibly improved mitochondrial function124 Can be used in chronic kidney disease123	Caution in cardiomyopathy/heart failure125 Increased risk for bone fractures126
GLP-1 agonists	Liraglutide Exenatide Semaglutide Lixisenatide Dulaglutide	Possibly improved mitochondrial function56 Antidiabetic and possibly improved neuroinflammation (WS)127 Possibly cardioprotective128	Gastrointestinal side effects Weight loss (could be benefit or risk) Risk of acute pancreatitis129 Risk of tachycardia130 Discontinue in chronic kidney disease stages 4–5123 Increased risk of medullary thyroid cancer in at risk individuals
Dipeptidyl-peptidase IV inhibitors	Sitagliptin Saxagliptin Alogliptin Linagliptin	Possibly improved mitochondrial function131 Linagliptin can be used in chronic kidney disease123	Unclear effect on hospitalizations for heart failure (mixed data)132 Risk of acute pancreatitis133 Risk of arthralgias134
Sodium-glucose cotransport 2 inhibitors	Dapagliflozin Empagliflozin Canagliflozin Ertugliflozin	Benefit in heart failure135	Possible risk of genitourinary infections136 Possible risk of urinary tract infections136 Euglycemic DKA Consider monitoring β-hydroxybutyrate (illness, poor intake, alcohol consumption, or decreased insulin doses)137 Measure serum β-hydroxybutyrate because urinalysis may not be as accurate.106–108 Discontinue in chronic kidney disease stages 3b-5.123

Data from Refs.^{14,53,56,63,67,68,79,95, 106–108, 115–137}

Fig. 2.

Mechanisms of monogenic diabetes. In this schematic of a pancreatic β cell, the genes known to cause monogenic diabetes are shown in red. Some mitochondrial disorders also are known to cause diabetes, as reviewed in mitochondrial diabetes section.

Diagnostic considerations and mechanisms

The most common genes affected in MODY are GCK, HNF4A, and HNF1A. Each displays unique clinical features.¹⁵ MODY 2 arises from dominant mutations in GCK, which increase the glucose threshold required for pancreatic β-cell insulin release. Patients with GCK mutations present with mild fasting hyperglycemia that typically does not progress with age, benefit from medical therapy, or result in end organ damage.¹⁵

Insulin Resistance Syndromes

In contrast to the more common insulin production counterparts, mutations in INSR cause Donohue syndrome (severe, neonatal insulin resistance) and Rabson-Mendenhall syndrome (severe insulin resistance that presents in childhood).⁴⁸ Lipodystrophies are congenital or acquired conditions that cause severe insulin resistance in the setting of a paucity of subcutaneous fat. They can be generalized or partial (on the basis of extent of deficits) and are associated with multiorgan system involvement.⁴⁹ Diagnosis relies on physical examination, including careful survey of subcutaneous adipose depots throughout the body. Individuals with generalized lipodystrophy can receive treatment with recombinant leptin therapy, which reduces the large insulin doses (3–5 times higher than typical total daily insulin dose requirements) required to obtain normoglycemia in these patients.⁵⁰ Recombinant leptin also mitigates comorbidities, including fatty liver disease and hypertriglyceridemia.⁵⁰

Treatment

Many treatment considerations for atypical DM are similar to those in typical forms of DM. Management is reviewed in Table 3.

MITOCHONDRIAL DIABETES MELLITUS

Background

Mitochondrial diseases are estimated to affect 1 in 5000 individuals and are caused by genetic defects that occur in either the mitochondrial DNA (mtDNA) (de novo or maternal inheritance) or the nuclear DNA (most commonly autosomal recessive) that encode protein constituents of mitochondria or proteins responsible for mitochondrial maintenance.⁵¹ The heterogeneity, variable expressivity, age independence, and multiorgan system involvement all often lead to delayed diagnoses.

Multiple potential endocrine complications can arise with mitochondrial disease. Foremost is DM, which has a prevalence of 11% to 15% in mitochondrial disorders (Table 2).⁵² Age of DM diagnosis on average is 32 years to 38 years but is highly variable, and increasing prevalence of mitochondrial DM with advancing age has been reported.^52,53

Table 2.

Overview of diabetes in mitochondrial disorders

Typical Underlying Genetic Mutations(s)	Mitochondrial Disease Clinical Syndrome	Percentage with Diabetes Mellitus (%)	Frequently Encountered Nonendocrine Manifestations	Other Associated Endocrinopathies: In Many of Them, High Prevalence of Risk Factors for Poor Bone Health62
mtDNA deletion syndromes
mtDNA deletion syndrome	Pearson syndrome63	Neonatal and/or infantile DM may occur	Macrocytic anemia, neutropenia, thrombocytopenia Renal tubular defects Liver disease Exocrine pancreatic insufficiency	Adrenal insufficiency
mtDNA deletion syndrome	Kearns-Sayre Syndrome (KSS)64–66	11–14	Retinitis pigmentosa Progressive external ophthalmoplegia Cardiac conduction abnormalities Cerebellar ataxia Muscle weakness Sensorineural hearing loss Renal tubular acidosis	Short stature (38%) Gonadal dysfunction (20%) Hypoparathyroidism Growth hormone deficiency Hypothyroidism Adrenal insufficiency Hyperaldosteronism Hypomagnesaemia Bone abnormalities
mtDNA sequencing mutations
MT-TL1 m.3243A>G	Mitochondrial Encephalopathy, Lactic acidosis, and stroke-like episodes (MELAS)67	38	Epilepsy, dementia, headaches, ataxia, cognitive deficits Lactic acidosis Stroke-like episodes Cardiomyopathy/cardiac conduction defects Myopathy, neuropathy Pigmentary Retinopathy/optic atrophy	Hypothyroidism (12%) Atypical growth and sexual maturation Dyslipidemia52
MT-TL1 m.3243A>G	Maternally Inherited Diabetes and Deafness (MIDD)67	38; nearly 100 have IGT by age 70 y68	Sensorineural hearing loss Macular retinal dystrophy Myopathy Ptosis Cardiac and renal disease Spectrum of MELAS	Short stature Growth hormone deficiency
MT-TK m.8344A>G (this mutation may cause Leigh syndrome)	Myoclonic epilepsy with ragged red fibers69	11	Myoclonus, muscle weakness, ataxia, seizures Sensorineural hearing loss Optic atrophy, ptosis, progressive external ophthalmoplegia Cognitive impairment Cardiomyopathy Recurrent lipomas	Hypothyroidism (2/34 in 1 case series) Hypogonadism (1/34)69
MT-TS2 m.12258C>A	MT-TS2–related mitochondrial disease	Approaches 10070	Retinitis pigmentosa Sensorineural hearing loss71	None reported to date
MT-TE m.14709T>C.72	Myoclonic epilepsy with ragged red fibers, MIDD	~60 12/20 reported (and 1 gestational DM)73	Congenital encephalomyopathy Retinitis pigmentosa Cardiomyopathy Juvenile or adult-onset myopathy74	None reported to date
Nuclear DNA disorders
WFS1 (primary lesion in endoplasmic reticulum)75 (AR or AD) CISD2 (WFS2) (AR)76	WS: historically considered a mitochondrial disorder77	10078	Optic nerve atrophy Sensorineural hearing loss (65%) Neurologic disabilities (60%) Urinary tract problems	Diabetes insipidus (70%) Hypogonadism
GAA triplet repeat in frataxin (FXN)79	Friedreich’s Ataxia (FA)	8–4056	Ataxia Cardiomyopathy Visual loss Hearing concerns Cognition spared	Short stature
Polymerase gamma (POLG)80	POLG-related mitochondrial disease spectrum (Alpers syndrome, childhood myocerebrohepatopathy spectrum, myoclonic epilepsy myopathy sensory ataxia, sensory ataxic neuropathy with dysarthria and ophthalmoparesis, ataxia neuropathy spectrum, and chronic progressive external ophthalmoplegia)	Case reports of DM, prevalence unknown	Ataxia, seizures, neuropathy Leukodystrophy Optic atrophy, CPEO Cardiac arrhythmias/cardiomyopathy Liver failure, gastrointestinal dysmotility Gastrointestinal dysmotility Myopathy	Adrenal insufficiency Hypothyroidism.81 Hypogonadism82
RRM2B	RRM2B-related mtDNA maintenance disorder (rarely can cause childhood KSS and mitochondrial neurogastrointestinal encephalomyopathy)	Case reports of DM, prevalence unknown	Adult-onset ophthalmoparesis Myopathy Neurologic complications Sensorineural hearing loss Renal tubulopathy Gastrointestinal disturbance83	Hypothyroidism Hypoparathyroidism Hypogonadism Short stature83
MPV1753,84	MPV17-related mtDNA maintenance disorder	Case reports of DM, prevalence unknown	Neurohepatopathy Failure to thrive Lactic acidosis Gastrointestinal dysmotility84	Hypoglycemia Hypoparathyroidism85
TYMP86	Mitochondrial neurogastrointestinal encephalomyopathy	~4 4/10286	Leukoencephalopathy Neuropathy Sensorineural hearing loss Weight loss Gastroparesis pseudo-obstruction	Dyslipidemia
ELAC287	Combined oxidative phosphorylation deficiency type 17	Case reports of DM, prevalence unknown	Cognitive deficiencies Failure to thrive Hypertrophic cardiomyopathy Myopathy Typically, infantile onset	None reported
GFM288	Leigh syndrome; combined oxidative phosphorylation deficiency type 39	Case reports of DM, prevalence unknown	Microcephaly Axial hypotonia, peripheral hypertonia Developmental delays/regression Brain magnetic resonance imaging abnormalities Seizures Contractures Arthrogryposis multiplex congenita	Hypoglycemia
TRIT189	Combined oxidative phosphorylation deficiency 35	Case reports of DM, prevalence unknown	Microcephaly Abnormal brain magnetic resonance imaging Myoclonic epilepsy Developmental delay Optic disc hypoplasia Cardiac septal defects	None reported
Additional mitochondrial mutations that cannot yet be clearly linked to diabetes
MT-TK m.8296A>G90	Found in 0.9% of 1000 patients with DM but may be a benign polymorphism91
MT-ND6 m.14577T>C92	Found in 3/253 patients with DM but also has a high frequency in the general population.
OPA193	Diabetes reported but not at rates greater than in typical DM.
RNASE1H	Genetic changes associated with concurrent mitochondrial disorder and autoimmune diabetes.
HNF1B	Reviewed in the MODY section of this article but may be related to mitochondrial dysfunction.94

Abbreviations: AD, autosomal dominant; AR, autosomal recessive.

Data from Refs.^{52,53,56,62–94}

Brief Overview of Mechanisms

Impaired insulin secretion

In the setting of primary mitochondrial impairment, decreased oxidative phosphorylation capacity may lead to an increased burden of free radicals that contributes to pancreatic β-cell impairment.⁵⁴ In animal studies, administration of streptozotocin, which inhibits mitochondrial replication, transcription, and oxidative phosphorylation capacity, has been shown to diminish glucose-stimulated insulin release from islets.⁵⁵ In some genetic disorders affecting mitochondria, including Friedreich ataxia (FA),⁵⁶ decreased β-cell mass also may contribute to insulin secretion defects.

Insulin resistance

Some studies of mitochondrial DM have demonstrated skeletal muscle insulin resistance even when β-cell function is not yet impaired.⁵⁷ The detailed pathophysiology of muscle insulin resistance in mitochondrial disorders is the focus of ongoing investigation. Increased oxidative stress may be one cause of tissue-specific insulin resistance in the setting of decreased mitochondrial oxidative phosphorylation capacity.^54,58 Importantly, in some settings, increased mitochondrial respiration can be protective against diabetes. An animal model of ANT1 deficiency, a disorder affecting adenosine triphosphate transport, illustrates this phenomenon.⁵⁹

Additional mechanistic considerations, including the role of mitochondria in the development of typical forms of DM⁶⁰ and the role of hyperglycemia in mitochondrial dysfunction,⁶¹ are beyond the scope of this overview.

Diagnosis

General and subtype specific expert consensus guidelines regarding screening for mitochondrial DM exist. General guidelines published by Newcastle University in the United Kingdom recommend screening with HbA_1C at diagnosis of mitochondrial disease and annually thereafter. Additionally, random glucose and HbA_1C should be obtained if patients endorse new or worsening polyuria or polydipsia; an OGTT is recommended for individuals with HbA_1C between 6.0% and 6.5%.⁹⁵ Some mitochondrial disorders have disease-specific recommendations. For example, FA clinical management guidelines note that HbA_1C alone may be an inadequate screening/diagnostic test for FA-related DM and recommend fasting blood glucose measurement annually.⁹⁶ Regardless of specific disease, all patients and families should be counseled about DM risk and symptoms that should prompt contacting the care team.

DM can be the presenting feature in mitochondrial diseases. Individuals with Wolfram syndrome (WS) can present first with nonautoimmune, insulin-deficient DM (average age 6 years) and subsequently are diagnosed with WS when optic atrophy manifests.⁷⁷ Similarly, in individuals with maternally inherited diabetes and deafness (MIDD), although hearing loss often precedes DM, DM can be the first presenting feature. Approximately 1% of individuals with MIDD initially were misclassified as having T1D or T2D.⁹⁷ DM as the first presenting feature of mitochondrial disease has been reported even in mitochondrial disorders whose initial manifestation typically is neurologic, such as FA.⁹⁸

Diabetes presentation, although often insidious, can be variable within and across the various mitochondrial disorders. Percentages of individuals with impaired glucose tolerance (IGT) vary among mitochondrial disorders (for example, at least 49% in FA and approaching 100% in MIDD by age 70 years).^56,68 Although not typical, DKA has been reported in FA,⁹⁹ mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)¹⁰⁰; Kearns-Sayre syndrome (KSS)¹⁰¹; and WS¹⁰² and hyperosmolar hyperglycemia has been documented in KSS.⁶⁴ One of these reports is of a child who died from DKA after oral corticosteroids, which can precipitate or worsen hyperglycemia.¹⁰³ Collaborating clinicians should be alert to DM risk and potential need for blood glucose monitoring when prescribing medications associated with hyperglycemia. Mitochondrial-related myopathy also may increase the risk of DKA-related respiratory failure.¹⁰⁴

Fig. 1 reviews when to consider mitochondrial DM evaluation.

Management

Established clinical guidelines for management of T1D and T2D should be the starting place for management decisions in atypical DM. Some glucose-lowering medications, however, carry risks related to kidney disease and/or heart failure,¹⁰⁵ comorbidities that are common in mitochondrial disorders. Additionally, risks for lactic acidosis, arrhythmias, pancreatitis, and ketoacidosis are important to consider.

The UK Newcastle guidelines emphasize that if ketones are present and/or C peptide is low, then insulin is the starting treatment of choice.⁹⁵ The authors recommend measuring serum β-hydroxybutyrate instead of urine acetoacetate in patients with mitochondrial diabetes at risk for ketoacidosis. In individuals with mitochondrial disorders, the accumulation of NADH relative to NAD⁺ in the setting of mitochondrial respiratory chain impairment shifts the ratio of acetoacetate to β-hydroxybutyrate in favor of β-hydroxybutyrate.^106,107 Therefore, urinary acetoacetate measurements could falsely underestimate the degree of ketosis in individuals with mitochondrial diabetes.¹⁰⁸

Case series of mitochondrial DM discuss the requirement for insulin but often do not mention whether other antidiabetic treatments were considered.^66,77 Oral antidiabetic agents have not been tested rigorously in this patient population. At the time of this publication, only insulin, metformin, and liraglutide are approved in populations aged less than 18 years. Ultimately, appropriate medical therapy requires individualized risks and benefits assessment (Table 3).

Lifestyle measures are important in management of mitochondrial DM but may be difficult to enact.¹⁰⁹ Current guidance recommends individualizing nutritional interventions and encouraging physical activity in typical DM. Extending these recommendations to individuals with mitochondrial DM appears reasonable, but evidence surrounding their efficacy is limited.¹¹⁰ Improving nutrition and physical activity also may be more difficult due to gastrointestinal manifestations,¹¹¹ nonambulatory status, decreased bone strength,⁶² cardiomyopathy,¹¹² and intellectual disability.¹¹³

CYSTIC FIBROSIS–RELATED DIABETES

Background

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene on chromosome 7, resulting in a defective or absent CFTR ion channel, increased airway fluid viscosity, and impaired mucociliary clearance. CFTR expression in the lung, intestine, and pancreas, among other tissues, explains the wide breadth of disease manifestations. The name cystic fibrosis, originated in the 1930s as a description of the fibrotic and cystic pancreas. For many years, therapies targeted mucus viscosity and infections, but the first successful modulator therapy aimed at correcting the CFTR defect has revolutionized advances in the disease.¹³⁸ With median age of survival approaching 50 years,¹³⁹ later manifestations of the disease are more relevant. CF-related diabetes (CFRD) affects 20% of adolescents and up to 50% of adults aged greater than 30 years¹⁴⁰ and is associated with worse pulmonary function, poorer nutritional status, and overall greater mortality.^141–144

Brief Overview of Mechanisms

While initially considered solely a product of collateral damage from the fibrotic and inflamed exocrine pancreas, CFRD now is understood to be multifactorial. β-cell defects—including dysfunction and total islet loss,^145,146 impairment in incretin signaling,^147,148 possible α-cell defects,¹⁴⁹ and T2D risk variants¹⁵⁰—all play important roles in disease development. Whether CFTR is expressed in β cells to contribute directly to insulin secretion defects remains a topic of debate.^145,151,152 Although this disease is wrought with inflammation/infection and corticosteroid exposure, the resulting insulin resistance is observed primarily in times of illness and is not considered a principal mechanism for CFRD.

The earliest clinical presentation of CF-related glucose abnormalities arises from loss of β-cell secretory capacity as manifested by declines in early-phase insulin secretion in response to meals and oral glucose load¹⁵³ and elevated plasma glucose at 1 hour (Fig. 3). Progressive insulin secretory defects lead to worsening hyperglycemia with fasting hyperglycemia as a late manifestation. Both pulmonary function and nutritional status decline in the years prior to CFRD onset and are associated with subtle glucose abnormalities defined as continuous glucose monitoring (CGM) time above glucose range.^154–156 These findings suggest CF-related glucose abnormalities occur on a clinically relevant continuum prior to CFRD diagnosis.

Fig. 3.

Plasma glucose (A) and insulin secretory rates (B) in response to the mixed-meal tolerance test in subjects with pancreatic insufficient (PI) CF. Individuals were categorized based on a preceding OGTT (EGI, early glucose intolerance [plasma glucose at 1 hour greater than or equal to 155 mg/dL and plasma glucose at 2 hours less than or equal to140 mg/dL]; NGT, normal glucose tolerance). Significant decline in β-cell secretory capacity is evident in PI-EGI. (From Nyirjesy SC, Sheikh S, Hadjiliadis D, et al. β-Cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose ≥155 mg/dL. Pediatr Diabetes. 2018;19(7):1173–1182; with permission.)

The impact of the newest modulator therapies currently is unknown. Promising improvements in insulin secretion in response to ivacaftor give hope that the landscape of CFRD may be changing.¹⁴⁸

Diagnosis

The Cystic Fibrosis Foundation recommends annual CFRD screening using an OGTT (1.75 g/kg, maximum 75 g) by age 10 years.^144,146 OGTT 1 hour greater than 155 mg/dL has been associated impaired β-cell secretory capacity and inconsistently greater declines in pulmonary function.^153,157 CGM currently is not recommended as a screening or diagnostic tool, given the lack of management recommendations for early derangements.¹⁵⁸

Other screening opportunities include blood glucose monitoring during the first 48 hours of acute illness/hospitalization and while on overnight enteral feedings. Stress-induced hyperglycemia lasting greater than 48 hours warrants CFRD diagnosis given associated worsened morbidity.¹⁴⁴ Blood glucose greater than 200 mg/dL during or after overnight feeds on 2 separate occurrences is diagnostic of CFRD.¹⁵⁹

Although HbA_1C greater than 6.5% remains diagnostic for CFRD and can be used for monitoring diabetes control; it is not recommended for screening purposes because it fails to capture early glucose abnormalities.^144,146,160 No thresholds for HbA_1C; fructosamine; 1,5-anhydroglucitol; and glycated albumin were sufficiently sensitive or specific to replace OGTT in identifying CFRD.¹⁶¹

Management Considerations

High caloric density and salt and fat consumption are recommended for people with CF, and a diagnosis of CFRD does not change these recommendations. Instead, patients should be instructed in carbohydrate counting and to modulate carbohydrate intake throughout the day.¹⁶² This approach may be relevant particularly in individuals experiencing reactive hypoglycemia after large glycemic loads.¹⁶³ Patients on enteral feed supplementation should receive full caloric formula and not low-glycemic dietary supplements.¹⁶⁴ Finally, sensitivity to patients when providing recommendations for nutritional modification is important: adequate weight gain and increased caloric intake are emphasized from a young age in this population and changes to nutritional habits may be overwhelming.

The mainstay of diabetes medical management is subcutaneous insulin, which benefits glycemic control and boasts anabolic properties that can improve nutritional status.¹⁶⁵ The most common regimen in individuals without fasting hyperglycemia includes multiple daily injections with rapid-acting insulin to cover meals.^146,165 Insulin sensitivity tends to be normal (requiring <0.5–0.8 U/kg/d) across the age continuum.¹⁶⁶ Basal insulin is required for individuals with fasting hyperglycemia but also sometimes is administered in the absence of fasting hyperglycemia.^146,165 Continuous subcutaneous insulin administration via an insulin pump for more individualized diabetes management also can be considered.

Early insulin treatment and other medical therapies have been studied in CF. Repaglinide treatment results in similar glycemic control to insulin but without body mass index (BMI) improvement, limiting its widespread application in this population.¹⁴⁰ Currently, the efficacy of glucagon-like peptide-1 (GLP-1) agonists in treating early incretin abnormalities is being evaluated, but potential concerns in CF include gastrointestinal symptoms and weight loss.¹⁶⁴

Hypoglycemia, in the absence of diabetes and insulin therapy, has been noted after long periods of fasting as well as postprandially.¹⁶⁷ Long-term implications of hypoglycemia remain unclear, with some studies demonstrating early glucose derangements and impaired early-phase insulin secretion concerning for β-cell function decline¹⁶³ but others suggesting that these individuals do not progress more rapidly to CFRD.¹⁶⁸

Microvascular complications are restricted to individuals with fasting hyperglycemia, and patients should be screened for retinopathy, microalbuminuria, and neuropathy starting 5 years after a diagnosis of CFRD.¹⁴⁶ Macrovascular complications have not been appreciated in CF. The contribution of decreased life expectancy and absence of other metabolic derangements, such as dyslipidemia, hypertension, and obesity, to the cardioprotection is unknown but requires further study in the changing landscape of CF.^169,170

Cystic Fibrosis–Related Diabetes Conclusions

CFRD is viewed as a spectrum of abnormal glucose tolerance with early abnormalities seen in early-phase insulin secretion followed by progressive β-cell decline. The etiology of CFRD development is multifactorial. Early diagnosis and treatment are crucial given implications for morbidity and mortality. At present, insulin therapy is paramount but investigations are geared at further understanding pathogenesis to suggest less burdensome treatment strategies.

SUMMARY

Providers should be suspicious for atypical DM, particularly in youth with a known condition that confers risk and in youth who lack both islet autoantibodies and classic signs of T2D. Strong family history of DM and conditions associated with atypical DM also are features that may prompt additional testing. Although some forms of atypical DM have clear treatment recommendations, many require an empiric evaluation of the patient’s presentation, associated conditions, and individualized risks in order to determine the best treatment. More studies are needed in the area of identification of subtypes, screening for detection, and treatment of atypical forms of DM.

KEY POINTS.

• Diagnosis of atypical diabetes requires attention to clinical presentation, specific testing, and personalized treatment based on genetic etiology and comorbidities.

• Atypical diabetes should be considered in patients with disorders associated with diabetes (eg, cystic fibrosis or mitochondrial disease) or age less than 25 years old with nonautoimmune diabetes and lacking typical type 2 diabetes mellitus characteristics.

• Comorbidities, such as deafness, history of hyperinsulinism, renal disease, and liver disease, in a patient with new-onset diabetes should prompt consideration of atypical diabetes.