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Monogenic Diabetes (Neonatal Diabetes Mellitus & MODY)

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What are monogenic forms of diabetes?

What is neonatal diabetes mellitus (ndm), what is maturity onset diabetes of the young (mody), how is monogenic diabetes diagnosed, what do i need to know about genetic testing and counseling, how is monogenic diabetes treated and managed, clinical trials.

The most common forms of diabetes, type 1 and type 2 , are polygenic, meaning they are related to a change, or defect, in multiple genes. Environmental factors, such as obesity in the case of type 2 diabetes, also play a part in the development of polygenic forms of diabetes. Polygenic forms of diabetes often run in families. Doctors diagnose polygenic forms of diabetes by testing blood glucose, also known as blood sugar, in individuals with risk factors or symptoms of diabetes.

Genes provide the instructions for making proteins within the cell. If a gene has a change or mutation, the protein may not function properly. Genetic mutations that cause diabetes affect proteins that play a role in the ability of the body to produce insulin or in the ability of insulin to lower blood glucose . People typically have two copies of most genes, with one gene inherited from each parent.

Some rare forms of diabetes result from mutations or changes in a single gene and are called monogenic. In the United States, monogenic forms of diabetes account for about 1 to 4 percent of all cases of diabetes. 1,2,3,4 In most cases of monogenic diabetes, the gene mutation is inherited from one or both parents. Sometimes the gene mutation develops spontaneously, meaning that the mutation is not carried by either of the parents. Most mutations that cause monogenic diabetes reduce the body’s ability to produce insulin, a protein produced in the pancreas that helps the body use glucose for energy.

Neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the two main forms of monogenic diabetes. NDM occurs in newborns and young infants. MODY is much more common than NDM and usually first occurs in adolescence or early adulthood.

Most cases of monogenic diabetes are incorrectly diagnosed. For example, when high blood glucose is first detected in adulthood, type 2 diabetes is often diagnosed instead of monogenic diabetes. If your health care provider thinks you might have monogenic diabetes, genetic testing may be needed to diagnose it and to identify which type. Testing of other family members may also be indicated to determine whether they are at risk for or already have a monogenic form of diabetes that is passed down from generation to generation. Some monogenic forms of diabetes can be treated with oral diabetes medicines (pills), while other forms require insulin injections. A correct diagnosis allows for proper treatment and can lead to better glucose control and improved health in the long term.

NDM is a monogenic form of diabetes that occurs in the first 6 to 12 months of life. NDM is a rare condition accounting for up to 1 in 400,000 infants in the United States. 4 Infants with NDM do not produce enough insulin, leading to an increase in blood glucose. NDM is often mistaken for type 1 diabetes, but type 1 diabetes is very rarely seen before 6 months of age. Diabetes that occurs in the first 6 months of life almost always has a genetic cause. Researchers have identified a number of specific genes and mutations that can cause NDM. In about half of those with NDM, the condition is lifelong and is called permanent neonatal diabetes mellitus (PNDM). In the rest of those with NDM, the condition is transient, or temporary, and disappears during infancy but can reappear later in life. This type of NDM is called transient neonatal diabetes mellitus (TNDM).

Clinical features of NDM depend on the gene mutations a person has. Signs of NDM include frequent urination, rapid breathing, and dehydration. 5 NDM can be diagnosed by finding elevated levels of glucose in blood or urine. The lack of insulin may cause the body to produce chemicals called ketones , resulting in a potentially life-threatening condition called diabetic ketoacidosis . Most fetuses with NDM do not grow well in the womb, and newborns with NDM are much smaller than those of the same gestational age, a condition called intrauterine growth restriction. After birth, some infants fail to gain weight and grow as rapidly as other infants of the same age and sex. Appropriate therapy may improve and normalize growth and development.

MODY is a monogenic form of diabetes that usually first occurs during adolescence or early adulthood. MODY accounts for up to 2 percent of all cases of diabetes in the United States in people ages 20 and younger. 3

A number of different gene mutations have been shown to cause MODY, all of which limit the ability of the pancreas to produce insulin. This leads to high blood glucose levels and, in time, may damage body tissues, particularly the eyes, kidneys, nerves, and blood vessels.

Clinical features of MODY depend on the gene mutations a person has. People with certain types of mutations may have slightly high blood sugar levels that remain stable throughout life, have mild or no symptoms of diabetes, and do not develop any long-term complications. Their high blood glucose levels may only be discovered during routine blood tests. However, other mutations require specific treatment with either insulin or a type of oral diabetes medication called sulfonylureas.

MODY may be confused with type 1 or type 2 diabetes. In the past, people with MODY did not generally have overweight, obesity, or other risk factors for type 2 diabetes, such as high blood pressure or abnormal blood fat levels. However, as more people in the United States become overweight or have obesity, people with MODY may also be overweight or have obesity.

Although both type 2 diabetes and MODY can run in families, people with MODY typically have a family history of diabetes in multiple successive generations, meaning MODY is present in a grandparent, a parent, and a child.

Genetic testing can diagnose most forms of monogenic diabetes. A correct diagnosis with proper treatment should lead to better glucose control and improved health in the long term.

Genetic testing is recommended if 6

• diabetes is diagnosed within the first 6 months of age
• diabetes is diagnosed in children and young adults, particularly those with a strong family history of diabetes, who do not have typical features of type 1 or type 2 diabetes, such as the presence of diabetes-related autoantibodies, obesity, and other metabolic features
• a person has stable, mild fasting hyperglycemia, especially if obesity is not present

Genetic testing for monogenic diabetes involves providing a blood or saliva sample from which DNA is isolated. The DNA is analyzed for changes in the genes that cause monogenic diabetes. Genetic testing is done by specialized labs.

Abnormal results can determine the gene responsible for diabetes in a particular individual or show whether someone is likely to develop a monogenic form of diabetes in the future. Genetic testing can be helpful in selecting the most appropriate treatment for individuals with monogenic diabetes. Testing is also important in planning for pregnancy and to understand the risk of having a child with monogenic diabetes if you, your partner, or your family members have monogenic diabetes.

Most forms of NDM and MODY are caused by autosomal dominant mutations, meaning that the condition can be passed on to children when only one parent carries or has the disease gene. With dominant mutations, a parent who carries the gene has a 50 percent chance of having an affected child with monogenic diabetes.

In contrast, with autosomal recessive disease, a mutation must be inherited from both parents. In this instance, a child has a 25 percent chance of having monogenic diabetes.

For recessive forms of monogenic diabetes, testing can indicate whether parents or siblings without disease are carriers for recessive genetic conditions that could be inherited by their children.

While not as common, it is possible to inherit mutations from the mother only (X-linked mutations). Also not as common are mutations that occur spontaneously.

More information about the genes that cause NDM and MODY, the types of mutations responsible for the disease (autosomal dominant, autosomal recessive, X-linked, etc.), and clinical features is provided in the American Diabetes Association Standards of Medical Care in Diabetes .

If you suspect that you or a member of your family may have a monogenic form of diabetes, you should seek help from health care professionals—physicians and genetic counselors—who have specialized knowledge and experience in this area. They can determine whether genetic testing is appropriate; select the genetic tests that should be performed; and provide information about the basic principles of genetics, genetic testing options, and confidentiality issues. They also can review the test results with the patient or parent after testing, make recommendations about how to proceed, and discuss testing options for other family members.

Treatment varies depending on the specific genetic mutation that has caused a person’s monogenic diabetes. People with certain forms of MODY and NDM can be treated with a sulfonylurea, an oral diabetes medicine that helps the body release more insulin into the blood. Other people may need insulin injections. Some people with MODY may not need medications and are able to manage their diabetes with lifestyle changes alone, which include physical activity and healthy food choices. Your physician and diabetes care team will work with you to develop a plan to treat and manage your diabetes based on the results of genetic testing.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and other components of the National Institutes of Health (NIH) conduct and support research into many diseases and conditions.

What are clinical trials, and are they right for you?

Clinical trials are part of clinical research and at the heart of all medical advances. Clinical trials look at new ways to prevent, detect, or treat disease. Researchers also use clinical trials to look at other aspects of care, such as improving the quality of life for people with chronic illnesses. Find out if clinical trials are right for you .

What clinical trials are open?

Clinical trials that are currently open and are recruiting can be viewed at www.ClinicalTrials.gov .

This content is provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. NIDDK translates and disseminates research findings to increase knowledge and understanding about health and disease among patients, health professionals, and the public. Content produced by NIDDK is carefully reviewed by NIDDK scientists and other experts.

The NIDDK would like to thank: Louis Philipson, M.D., Ph.D., University of Chicago, Department of Medicine, Endocrinology, Director, Kovler Diabetes Center

REVIEW article

Neonatal diabetes mellitus.

• 1 Paediatric Endocrinology, Gynaecology and Diabetology, Necker–Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, IMAGINE Institute, ENDO-European Reference Network Team, Paris, France
• 2 Faculty of Medicine, Université de Paris, Paris, France
• 3 INSERM U1016, Cochin Institute, Paris, France
• 4 Paediatric Endocrinology, Diabetology and Obesity Unit, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
• 5 Inserm UMR-1018-CESP, Necker–Enfants Malades University Hospital Paedopsychiatry Department, Cochin University Hospital Paediatrics Department, Institut Universitaire de France, Assistance Publique-Hôpitaux de Paris, Université de Paris, Paris, France
• 6 Genetics Department, Robert-Debré University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
• 7 INSERM U1138, Cordeliers Research Centre, Paris, France

Neonatal Diabetes (ND) mellitus is a rare genetic disease (1 in 90,000 live births). It is defined by the presence of severe hyperglycaemia associated with insufficient or no circulating insulin, occurring mainly before 6 months of age and rarely between 6 months and 1 year. Such hyperglycaemia requires either transient treatment with insulin in about half of cases, or permanent insulin treatment. The disease is explained by two major groups of mechanism: malformation of the pancreas with altered insulin-secreting cells development/survival or abnormal function of the existing pancreatic β cell. The most frequent genetic causes of neonatal diabetes mellitus with abnormal β cell function are abnormalities of the 6q24 locus and mutations of the ABCC8 or KCNJ11 genes coding for the potassium channel in the pancreatic β cell. Other genes are associated with pancreas malformation or insufficient β cells development or destruction of β cells. Clinically, compared to patients with an ABCC8 or KCNJ11 mutation, patients with a 6q24 abnormality have lower birth weight and height, are younger at diagnosis and remission, and have a higher malformation frequency. Patients with an ABCC8 or KCNJ11 mutation have neurological and neuropsychological disorders in all those tested carefully. Up to 86% of patients who go into remission have recurrent diabetes when they reach puberty, with no difference due to the genetic origin. All these results reinforce the importance of prolonged follow-up by a multidisciplinary pediatric team, and later doctors specializing in adult medicine. 90% of the patients with an ABCC8 or KCNJ11 mutation as well as those with 6q24 anomalies are amenable to a successful switch from insulin injection to oral sulfonylureas.

Diabetes mellitus in very young children or neonatal diabetes is a rare genetic disease (minimal incidence: 1 in 90,000 live births) with variations within different ethnic groups ( 1 – 3 ). It is defined by the presence of severe hyperglycaemia requiring treatment and occurs between the neonatal period and infancy. It occurs mainly before 6 months of age (155/173 probands in our published cohort) and rarely between 6 months and 1 year (18/173) ( 4 ). In the Finnish population for example, after 6 months of age, patients with diabetes had high HLA risk genotypes and islet autoantibodies, reflecting the autoimmune character of diabetes ( 5 ). This hyperglycaemia is associated with insufficient or no circulating insulin ( 3 ). Two clinical forms have been distinguished, based on the duration of the treatment: a so called “transient form” and a permanent form.

The disease is explained by two major groups of mechanism: malformation of the pancreas or abnormal function of the pancreatic β cell that secretes insulin (by poor insulin cell mass development or malfunction of a cell component or by destruction of the β cell) ( Table 1 ) (see Figure 1 for the normal functioning of the β cell).

Table 1 . Genetic causes of monogenic neonatal diabetes based on physiopathological mechanisms [excluding 6q24 locus abnormalities (MIM *601410, *603044, and *612192)].

Figure 1 . Mechanism of insulin secretion in response to glucose and glibenclamide.

Genetic Causes

Abnormal β cell function.

The most frequent genetic causes of neonatal diabetes with normal pancreas morphology are abnormalities of the 6q24 locus and mutations of the genes coding for the ATP-dependent potassium channel.

6q24 (MIM#601410 and 603044)

The first genetic causes identified were abnormalities of the 6q24 locus, which include paternal uniparental disomy of 6q24 (pUPD6), partial duplication of paternal 6q24 and relaxation of the maternal 6q24 imprinted locus. This locus contains a CpG island, presenting differential methylation depending on the parental origin (non-methylation on the paternal allele, methylation on the maternal allele) ( 6 ). To date, the methylation abnormality has not been found in the parents of affected children. Methylation is used to down-regulate gene transcription of the methylated allele. All these abnormalities lead to over-expression of imprinted genes located in 6q24, such as PLAGL1/ZAC (pleiomorphic adenoma gene-like 1) and HYMAI (Hydatidiform mole-associated and imprinted transcript), which are the most “likely” candidate genes ( 6 – 8 ). PLAGL-1 codes for a transcription factor involved in regulation of stopping the cell cycle and apoptosis and in induction of the receptor 1 gene for human pituitary adenylate cyclase-activating polypeptide (PACAP1, which is a potent stimulant of insulin secretion). The function of the HYMAI gene is unknown ( 9 ). The mechanism responsible for the diabetes could be linked to a developmental defect in the β cells but the fact that remission of the diabetes occurs means that an abnormality in β cell function cannot be ruled out ( 10 ). The 6q24 abnormalities are associated with “transient” neonatal diabetes ( 7 , 8 , 11 ).

The ZFP57 gene (MIM * 612192) is involved in maintaining methylation of the DNA during the very early stages of embryogenesis. It is localized at 6p22.1. Homozygous mutations leading to a lack of protein or non-functional protein are associated with widespread DNA hypomethylation, including hypomethylation of the 6q24 locus ( 12 ). However, there are patients who have a 6q24 methylation abnormality not due to mutations of this gene ( 12 ).

Mutations of the ABCC8 and KCNJ11 Genes Coding for the K ATP Channel: (MIM * 600509 and * 600937)

The ATP-dependent potassium channel (K ATP channel) plays a central role in stimulating insulin secretion by the pancreatic β cell in response to glucose. At low blood sugar levels (e.g., fasting), the K ATP channels are open (activated) and their activity maintains a hyperpolarized resting membrane potential (around −70 mV). A rise in blood sugar level (e.g., post-prandial) causes increased passage of glucose into the β cell. Glucose enters the glycolysis pathway, which increases the intracellular ATP concentration. This causes the K ATP channels to close (inhibition), which leads to the intracellular potassium accumulation that causes membrane depolarization. This depolarization activates the voltage-dependent calcium channels, leading to Ca 2+ ions entering the β cell, then enabling exocytosis of the secretion vesicles and release of insulin into the bloodstream ( Figure 1 ).

The K ATP channel is an octamer formed from two types of subunits: the Kir6.2 subunits form the channel selective for the incoming corrective potassium enclosed in SUR1 ion-channel regulator subunits ( 13 , 14 ). They are coded by the KCNJ11 and ABCC8 genes, respectively.

Activating mutations in one of these two genes are responsible for neonatal diabetes with normal pancreas morphology ( 15 – 17 ). They result in the K ATP channel remaining permanently open, so that it no longer controls membrane potential in response to glucose and therefore blocks the event cascade that leads to insulin release.

Mutations of the Insulin Gene (INS) (MIM * 176730)

The third cause of neonatal diabetes, by frequency, is mutations of the insulin gene ( INS ). The majority are heterozygous mutations affecting the structure of preproinsulin; these are transmitted in an autosomal dominant manner ( 18 , 19 ). The abnormal proinsulin undergoes degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum (ER) stress and β cell death. This process has been described in mouse models ( 20 ) and in man ( 21 , 22 ). Recent evidence suggests that INS mutations do not necessarily lead to beta-cell death but rather the chronic ER stress interferes with beta-cell growth and development ( 23 ).

Some mutations alter expression of the protein. They are transmitted in a recessive manner, in the majority of cases in consanguineous families. These mutations affect the insulin promoter directly of by mutation in factor that enhances its activity ( 24 , 25 ).

Mutations of the Glucokinase Gene (MIM * 138079)

Glucokinase is responsible for the first step of glucose metabolism in the β cell. It acts as a “sensor” of blood glucose, making it possible to control the quantity of insulin secreted. Nonsense mutations of the glucokinase gene cause MODY 2 (Maturity onset diabetes in the youth type 2), which usually presents as moderate hyperglycaemia ( 26 ). Transmission is heterozygous. In the homozygous state, these nonsense mutations cause neonatal diabetes by complete deficiency of glucokinase-mediated glycolysis ( 27 ). This is not a frequent cause of neonatal diabetes ( 28 , 29 ). However, an assay of the fasting blood glucose concentration is required from both parents, particularly if there is a history of gestational diabetes. The discovery of discreet glucose intolerance in both parents should therefore lead to a search for glucokinase gene mutations.

Abnormal Pancreas Morphology

Several genes are linked to neonatal diabetes with abnormal pancreas morphology and precise description is beyond the scope of this chapter (see Table 1 for a brief information). These genes are involved in development of the pancreas at various stages in early morphogenesis. These neonatal diabetes cases may be associated with a deficiency of the exocrine pancreas, based on the severity of pancreatic damage or to other congenital malformations. Mutation of the RFX-6 gene deserves a specific comment. The RFX-6 transcription factor is involved in the differentiation of beta-cells in the pancreas during embryonic development of the pancreas. It is also expressed in mature cells where it has a role in regulating insulin transcription and secretion. It actually controls the expression and activation of calcium channels and its inactivation alters insulin secretion in response to glucose. A few cases of neonatal diabetes have been reported. Patients display developmental abnormalities of the pancreas and of the digestive tract. The mechanism is linked to both a developmental and a functional disorder of the endocrine pancreas. Transmission is autosomal recessive ( Table 1 ).

Autoimmune Neonatal Diabetes Mellitus

Most patients diagnosed with diabetes between 6 and 12 months of age will have the “typical” type 1 diabetes mellitus seen in older children with positive autoantibodies against the beta cell. Autoimmune diabetes is very rare before 6 months of age and will most often be linked to specific causes.

IPEX Syndrome ( Table 1 )

Mutations of the FOXP3 gene may be responsible for enteropathy, immune dysregulation and polyendocrinopathy. It is a cause of neonatal diabetes associated with early autoimmunity directed against the beta cells of the pancreas. This diagnosis should be considered in male infants presenting diabetes associated with immune deficiency and/or severe infections. Immunosuppressant treatment can be considered (serolimus, corticosteroids) but bone marrow transplant must be considered as soon as the child's clinical condition allows. Insulin treatment will be combined with specialized nutritional management (parenteral ± enteral nutrition) before and after the transplant. It should be noted that, while correcting immune deficiencies, this will not eliminate the diabetes.

Down Syndrome and Neonatal Diabetes

Patients with Down syndrome (DS) resulting from trisomy 21 are more likely to have childhood diabetes mellitus. Professor Hattersley's group found 13 infants affected by DS who were diagnosed with diabetes before the age of 6 months. Trisomy 21 was seven times more likely in their PNDM cohort than in the general population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected). Known PNDM genes explains 82.9% of non-DS PNDM in their work. None of the 13 DS-PNDM patients had a mutation in those genes. The conclusion from this work is that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated ( 30 ).

Other mutations, such as the activating STAT3 mutations have been described which cause neonatal diabetes associated with beta-cell autoimmunity ( Table 1 ).

Clinical Description

There are two clinical forms of neonatal diabetes based on the duration of insulin-dependency. In the transient form, treatment may be stopped at any time from the first weeks of life to 5 years of age ( 4 ). In the permanent forms, life-long treatment is necessary.

The clinical difference between transient and permanent neonatal diabetes is not always underpinned by distinct molecular mechanisms. Abnormalities of the 6q24 locus are exclusively linked to transient neonatal diabetes. However, mutations of the ABCC8, KCNJ11 , and INS genes are linked to both permanent and transient forms ( 17 , 18 , 25 ). Other genetic causes are associated with permanent neonatal diabetes.

Neonatal diabetes is usually diagnosed before 6 months of age. However, the age of diagnosis varies depending on genetic causes: diabetes due to a 6q24 locus abnormality appears before the age of 1 month in 93% of cases and before the age of 3 months in 100% of cases. In ABCC8 and KCNJ11 gene mutations, it appears before the age of 1 month in 30% of cases and between 1 and 6 months in 66% of cases ( 4 ).

At birth, patients have a birth-weight below the 10th percentile in 62% of cases ( 4 ), highlighting the crucial role of insulin secretion in fetal growth. This intrauterine growth retardation is found in all genetic groups with a greater proportion in patients with a 6q24 abnormality than those carrying a ABCC8 or KCNJ11 mutation (92 vs. 48%, p < 0.001) ( 4 ).

Half of patients with a detectable pancreas by ultrasound experience remission from the diabetes in our cohort ( 4 ). This occurs at the age of about 4 months. There is a difference depending on the genetic cause. Patients with a 6q24 locus abnormality are in remission before the age of 1 year in 97% of cases (median age 14 weeks) while remission may go as far as the age of 5 years in patients with an ABCC8 or KCNJ11 mutation (median age 39 weeks) ( 4 , 31 ). Patients with a rare recessive mutation of the INS gene have remission at a median age of 12 weeks ( 24 ), whereas the majority of the INS gene mutations are dominant and they never go into remission. The diabetes frequently relapses (in up to 86% of cases) at the onset of puberty, probably due to the insulin resistance of puberty ( 4 , 32 ). There is no difference between the genetic groups.

Depending on the genetic cause, patients with neonatal diabetes may have other clinical signs associated with diabetes ( Table 1 ).

In neonatal diabetes with normal pancreas morphology, there are associated neurological disorders and developmental defects. Approximately 25% of patients with a mutation of the ABCC8 or KCNJ11 genes have neurological disorders ranging from psychomotor disorders to delayed cognitive development associated with severe epilepsy (DEND syndrome: Developmental delay, Epilepsy, and Neonatal Diabetes) ( 33 ). In addition, we have shown that when patients undergo detailed neuro-psychomotor and neuropsychological tests, an attention deficit or language disorder extending as far as dyslexia is found in 100% of cases ( 4 ).

Patients with a 6q24 locus abnormality may have developmental defects (macroglossia, umbilical hernia, cardiac malformations, renal and urinary malformations, non-autoimmune anemia, hypothyroidism with gland in situ ) and neurological disorders ( 4 , 11 ).

In neonatal diabetes with abnormal pancreas morphology or with β cell destruction, the associated malformations depend on the genetic causes and are often grouped into defined syndromes ( Table 1 ). Figure 2 illustrates a diagnostic strategy by molecular biology.

Figure 2 . Molecular biology approach to neonatal diabetes ( 44 ).

Recent long-term follow-up data in TNDM support a decrease in maximal insulin secretion capacity to both glucose and arginine stimuli that reflect low insulin mass ( 34 ). This study also showed that, regardless of the underlying genetic abnormalities or the duration of diabetes, TNDM was associated with learning difficulties at school. The high relapse rate and absence of identified predictors of relapse in TNDM suggest a need for an HbA1c assay at least every 2 years throughout childhood and for an HbA1c assay and oral glucose tolerance test every year throughout adolescence ( 34 ). During childhood, close attention should be directed to education and neurodevelopmental milestones, in TNDM patients with and without diabetes ( 34 ).

Therapeutic Aspects

Drug treatment.

Due to the early onset and associated delayed intrauterine retardation, patients with neonatal diabetes very often receive their initial treatment in a neonatal department. The initial treatment aims to rebalance carbohydrate metabolism. It should be started immediately following diagnosis. The treatment consists of the balance between a calorie and carbohydrate intake necessary to restore normal weight without being excessive to avoid the risk of future insulin resistance (15–18 g/kg/d carbohydrate) and sufficient insulin-based treatment to achieve the correct metabolic equilibrium. Restricting intake below the nutritional recommendations for children with low birth weight is ineffective given the physiopathology of circulating insulin deficiency.

Insulin-based treatment is difficult to manage due to the very low weight. The therapeutic margins between hypoglycemia and hyperglycemia are small, and both are harmful for neurological development of the newborn. Using an insulin pump with or without dilution of the insulin to 1:10 in 0.9% NaCl (or with a bona-fide diluent if available) can sometimes improve manageability of the insulin during the first weeks of life ( 35 , 36 ). Blood glucose meters must be able to give a reliable measurement of capillary blood sugar level with the smallest possible quantity of blood (e.g., 0.3 μl blood). Few “conventional” blood glucose meters meet this criterion. Conventional capillary measurements can be done on the side edge of all the fingers, using auto-lancets offering variable pricking depths. This offers the advantage of sparing newborns' heels. An alternative is to use continuous glucose sensors, either isolated or combined with an insulin pump. In addition to enabling rapid access to interstitial blood glucose (they provide a proxy but do not actually measure the blood glucose value), they can now be coupled to the insulin pump, making it possible to activate the system to stop the insulin pump during hypoglycemia or before it occurs. They also have the advantage of minimizing the number of pricks of the skin. Used under suitable hygiene conditions, there is no increase in skin infections. It is advisable to involve experienced clinicians when treating the child and using these techniques.

Patients with ABCC8 or KCNJ11 mutations are treated successfully using hypoglycemic sulfonylureas, which act by binding to the regulator SUR1 subunit of the potassium channel ( 37 ) ( Figure 1 ). The mutated channels remain sensitive to sulfonylureas in 90% of cases, having an inhibitory effect on the potassium channel of the pancreatic β cell and restoring insulin secretion in response to a meal ( 38 ). Sulfonylurea therapy appears to be safe and often successful in neonatal diabetes patients before genetic testing results are available ( 39 ). An empiric inpatient trial of sulfonylurea can be therefore considered ( 39 ). However, obtaining a genetic diagnosis remains imperative to inform long-term management and prognosis.

It has now been demonstrated that treatment with Sulfonylureas provide a better metabolic equilibrium than insulin by normalizing the HbA1c while strongly reducing the incidence of hypoglycemia in cases of neonatal diabetes with ABCC8 or KCNJ11 mutations. It was also shown recently that hypoglycemic sulphonylureas were able to improve neurological, neuropsychological and visuomotor impairment if they are introduced early in the child's life ( 33 , 40 , 41 ). Finally, a recent study has shown that it could sometimes be used successfully to replace insulin in neonatal diabetes associated with chromosome 6 methylation abnormalities ( 42 ). This emphasizes the importance of making a genetic diagnosis rapidly after diagnosing neonatal diabetes, and especially the early introduction of sulphonylureas. The clinician's aim will be to treat the child with the maximum dose that normalizes blood glucose levels (pre-prandial target: 70–120 mg/dL—post-prandial target: 100–145 mg/dL) without causing hypoglycemia, in order to optimize the drug's effect on the central nervous system. Sulphonylureas are currently only available as a 5 mg tablet and are not licensed for indications in neonatal diabetes. However, glibenclamide has recently obtained the orphan-drug indication from the European Medicine Agency (EMA) in neonatal diabetes. Unlicensed administration is currently achieved by parents through crushing and extemporaneous dilution of the tablets. However, the crushed tablets are poorly soluble in water, which may lead to variations in the dosage actually received by the child. To resolve this problem, a sulphonylurea suspension called Amglidia R has demonstratable efficacy in this indication ( 43 ) and has recently obtained a European Marketing Authorization; it has been available in France under a temporary authorization for use (ATU: Autorisation Temporaire d'Utilization) since 2019. It will enable dosages to be adapted more accurately.

An Appendix added to this text describes succinctly the practical aspects of the switch from insulin injection to the glibenclamide suspension licensed in European Union for children and refers to the official summary of product characteristics for detailed information.

Importance of the Genetic Diagnosis

Genetic analyses enables the diagnosis of monogenic diabetes in nearly 83% of diabetes diagnosed before the age of 6 months ( 30 ). This genetic diagnosis is essential as it will both influence the therapeutic treatment and make it possible to predict potential diabetes-related complications or illnesses. Genetic analyses must be carried out when diagnosing diabetes mellitus in all of the following children: age <6 months when diabetes mellitus is detected, or between 6 months and 1 year if extra-pancreatic features and/or no evidence of pancreas autoimmunity and/or multiple autoimmune disorders or unusual family history or associated congenital defects ( Figure 2 ) ( 44 ). Testing should not be delayed until other symptoms of the disease appear or potential remission of the disease. It is also of utmost importance to identify if the sulfonylureas can be introduced successfully as high-dose sulfonylurea therapy has been shown to be an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy has been shown to be safe and highly effective, maintaining excellent glycemic control for at least 10 years ( 45 ).

Neonatal diabetes is a model of rare human genetic disease, important in the understanding of the development and function of the pancreatic β cell, and in helping to resolve the pathophysiology of more frequent adult diabetes, such as type 2 diabetes. Neonatal diabetes is often associated with specific neuropsychological or developmental disorders of underlying genetic causes. A multidisciplinary approach is therefore essential. All clinicians called upon to treat a patient with neonatal diabetes should look for these clinical signs. Knowing the natural history and complete phenotype of this disease makes it possible, firstly, to offer patients better treatment and, secondly, to broaden the scope of genetic analyses to genes involved in the development and function of other organs. Long-term follow-up should be implemented, including for the so-called “transient” forms of neonatal diabetes.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Conflict of Interest

MP is a scientific advisor for AMMTEK.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We were grateful to Prof. Paul Czernichow, Paris, France, for his active participation in our neonatal diabetes project. We thank Mme. Nathalie Pouvreau at the Robert Debré Hospital, Paris, for the biological diagnosis and the support of the bank. We also thank all clinicians in France and abroad, as well as the children and their families, who trust us in this field.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2020.540718/full#supplementary-material

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Keywords: neonatal diabetes mellitus, chromosome 6q24 abnormality, associated malformations, neuropsychological disorder, KCNJ11 (Kir6.2), ABCC8, sulfonylurea receptor (SUR1)

Citation: Beltrand J, Busiah K, Vaivre-Douret L, Fauret AL, Berdugo M, Cavé H and Polak M (2020) Neonatal Diabetes Mellitus. Front. Pediatr. 8:540718. doi: 10.3389/fped.2020.540718

Received: 05 March 2020; Accepted: 13 August 2020; Published: 30 September 2020.

Reviewed by:

Copyright © 2020 Beltrand, Busiah, Vaivre-Douret, Fauret, Berdugo, Cavé and Polak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Michel Polak, michel.polak@aphp.fr

† These authors share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Neonatal Diabetes Mellitus: An Update on Diagnosis and Management

Affiliations.

• 1 Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, MC 5053, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
• 2 Monogenic Diabetes Registry, University of Chicago Medicine, Kovler Diabetes Center, 900 East 57th Street, Chicago, IL 60637, USA.
• 3 Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Kovler Diabetes Center, The University of Chicago, 900 East 57th Street, Chicago, IL 60637, USA. Electronic address: [email protected].
• PMID: 29406006
• PMCID: PMC5928785
• DOI: 10.1016/j.clp.2017.10.006

Neonatal diabetes mellitus is likely to be due to an underlying monogenic defect when it occurs at less than 6 months of age. Early recognition and urgent genetic testing are important for predicting the clinical course and raising awareness of possible additional features. Early treatment of sulfonylurea-responsive types of neonatal diabetes may improve neurologic outcomes. It is important to distinguish neonatal diabetes mellitus from other causes of hyperglycemia in newborns. Other causes include infection, stress, inadequate pancreatic insulin production in preterm infants, among others. This review explores the diagnostic approach, mutation types, management, and clinical course of neonatal diabetes.

Keywords: Genetic; Glyburide; Insulin; Monogenic diabetes; Neonatal diabetes.

Copyright © 2017 Elsevier Inc. All rights reserved.

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Mechanisms of overexpression of imprinted…

Mechanisms of overexpression of imprinted genes causing 6q24-related neonatal diabetes. Diabetes in all…

Algorithm for considering sulfonylurea trial.

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• Review Article
• Published: 29 November 2011

Management of diabetes mellitus in infants

• Beate Karges 1 ,
• Thomas Meissner 2 ,
• Andrea Icks 3 ,
• Thomas Kapellen 4 &
• Reinhard W. Holl 5  

Nature Reviews Endocrinology volume  8 ,  pages 201–211 ( 2012 ) Cite this article

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• Paediatrics
• Therapeutics
• Type 1 diabetes

Diabetes mellitus diagnosed during the first 2 years of life differs from the disease in older children regarding its causes, clinical characteristics, treatment options and needs in terms of education and psychosocial support. Over the past decade, new genetic causes of neonatal diabetes mellitus have been elucidated, including monogenic β-cell defects and chromosome 6q24 abnormalities. In patients with KCNJ11 or ABCC8 mutations and diabetes mellitus, oral sulfonylurea offers an easy and effective treatment option. Type 1 diabetes mellitus in infants is characterized by a more rapid disease onset, poorer residual β-cell function and lower rate of partial remission than in older children. Insulin therapy in infants with type 1 diabetes mellitus or other monogenic causes of diabetes mellitus is a challenge, and novel data highlight the value of continuous subcutaneous insulin infusion in this very young patient population. Infants are entirely dependent on caregivers for insulin therapy, nutrition and glucose monitoring, which emphasizes the need for appropriate education and psychosocial support of parents. To achieve optimal long-term metabolic control with low rates of acute and chronic complications, continuous and structured diabetes care should be provided by a multidisciplinary health-care team.

Diabetes mellitus in infants and children differs in etiology, clinical presentation and therapeutic options; heterogeneous etiologies of diabetes mellitus in infancy include genetic abnormalities, developmental defects and autoimmune disease

Monogenic forms of neonatal diabetes mellitus almost always occur in the first 6 months of life and very rarely after 12 months; onset of diabetes mellitus in infants aged >6 months is mostly due to type 1 diabetes mellitus (T1DM)

Infants with T1DM exhibit rapid disease onset, poor residual β-cell function and a low rate of transient recovery

Insulin is preferentially provided by continuous subcutaneous infusion

Treatment with sulfonylurea is possible in most patients with mutations in the genes that encode the ATP-sensitive inward rectifier potassium (K ATP ) channel

Special needs of infants with diabetes mellitus include comprehensive education of caregivers and provision of ongoing diabetes care

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Acknowledgements

The authors' work was supported by the BMBF Kompetenznetz Diabetes Mellitus (Competence Network for Diabetes Mellitus) funded by the Federal Ministry of Education and Research (FKZ 01GI0859).

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Beate Karges

Department of General Pediatrics and Neonatology, University Children's Hospital, Heinrich Heine University of Düsseldorf, Moorenstraße 5, Düsseldorf, D-40225, Germany

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Department of Public Health and German Diabetes Center, Heinrich Heine University of Düsseldorf, Moorenstraße 5, Düsseldorf, D-40225, Germany

Andrea Icks

Department of Pediatrics, University of Leipzig, Liebigstraße 20a, Leipzig, D-04103, Germany

Thomas Kapellen

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Karges, B., Meissner, T., Icks, A. et al. Management of diabetes mellitus in infants. Nat Rev Endocrinol 8 , 201–211 (2012). https://doi.org/10.1038/nrendo.2011.204

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• ajp-v1-id1004

Introduction

Case report.

Austin J Pediatr. 2014;1(1): 1004.

A Case of Neonatal Diabetes Presentation, Diagnosis and Management

Michael Yafi*

Division of Pediatric Endocrinology, University of Texas Houston Health Science Center, USA

*Corresponding author: Michael Yafi, Division of Pediatric Endocrinology, University of Texas Houston Health Science Center, 6431 Fannin Street, Suite 3.122, Houston, TX 77030, USA

Received: April 18, 2014; Accepted: May 19, 2014; Published: May 20, 2014

We present a case of neonatal diabetes with special focus on the diagnostic therapeutic and education problems faced by the pediatric endocrinology team (physicians, nurses and diabetes educators) during the hospital course.

Keywords: NDM: Neonatal Diabetes Mellitus

Neonatal diabetes mellitus (NDM) is an extremely rare presentation of diabetes. Affected infants are often found to be hyperglycemic (but rarely ketotic). Once considered a single disease, neonatal DM is now known to be caused by mutation affecting insulin synthesis and release, and by several mutations causing severe insulin resistance. Knowing the cause is important to selection of appropriate therapy. The therapy is also different from the typical pediatric because of size and diet. Training the family to care for the diabetic neonate is challenging for all. This case report will review the presentation, work up needed to reach the diagnosis, and the management plan and goals.

A preterm male infant was born at 37 weeks’ gestation, weighing 1565 grams. His mother is a 25 year old G2P0010. The mother denied any history of diabetes. The baby’s parents were first cousins of Pakistani origin. Her pregnancy was complicated by intrauterine growth retardation (IUGR) and low amniotic fluid index score (AFI). Labor was induced because of severe IUGR.

The APGAR scores were 8 at 1 minute and 9 at 5 minutes. Patient was admitted to the neonatal intensive care unit because of the severely wasted appearance. On physical examination at birth, temperature was 96.5°–97.1° F, heart rate 118, respiratory rate 31, and blood pressure 83⁄48. The patient was very pale with light skin; the head was normocephalic without deformities. Cardiovascular and respiratory examinations were normal. The abdomen was soft, not distended, with a 3 vessel cord. The genitourinary examination showed bilateral descended testicles. The neurological examination showed excellent tone. Weight, length and FOC were below 3rd percentile.

Initial glucose levels were 85,81,91 mg⁄dl

Initial documented central glucose level was 175 mg⁄dl, but at 24 hours of life patient started having hyperglycemia with central glucose measurements of 697 and 843 mg⁄dl. At the age of 25 hours, an insulin drip was started at 0.1 units ⁄Kg⁄h and the pediatric endocrinology team was consulted.

I – Medical Workup

A. laboratory work.

• Central glucose level: The first three levels were 175–697– 843 mg⁄dl
• Insulin level (obtained after starting insulin drip) was 0.5 IU⁄ml at day 2 of life (normal fasting range 2–13 iu⁄ml)
• C–peptide levels (obtained after starting insulin drip) was 0.02 ng⁄ml at day 2 of life and less than 0.05 ng⁄ml at day 4 of life (normal levels 0.5–2.7 ng⁄ml)
• Lipid panel, liver enzymes, electrolytes were normal
• Hemoglobin A1C level obtained at day 29 of life was 6.3 %

B. Radiology Studies

Abdominal ultrasound showed no pancreatic abnormalities.

C. Genetic Testing

The neonatal diabetes mellitus by Athena Diagnostic was obtained. This test can detect mutations (point mutations, deletions, insertions and re–arrangements) in the coding sequences of the most common genes that are known to cause this condition including:

Glucokinase (GCK)

Potassium channel J11 (KCNJ11)

ATP–binding cassette transporter subfamily C member 8 (ABCC8)

Insulin (INS)

Insulin promoter factor 1 (IPF1)

The methodology uses Polymerase Chain Reaction (PCR), DNA sequencing of entire protein coding regions of genes.

The result of this DNA sequencing of the most common genes causing neonatal diabetes (IPF1, GCK, KCnJII and ABCC8) was unremarkable. However, a homozygous intronic mutation was found in the insulin gene:

No other abnormal variants were detected. Therefore, this was assumed to be the cause of neonatal diabetes. The parents were offered testing for the same mutation but declined.

II � Management plan and goals

At the seventh day of life, patient started feeding on breast milk with some added formula (Neosure 22). He was able to feed every 3 hours. At that time we changed the insulin therapy from the insulin drip to basal bolus subcutaneous insulin synchronized with feeds, as follows:

• Insulin glargine (r DNA origin) 0.25 units daily
• Insulin lispro 0.25 units every six hours (every other feeds) for glucose levels 300–450 mg⁄dl and 0.5 units for glucose levels above 450 mg⁄dl

The hospital pharmacist was able to dilute insulin to reach low concentration. Each 1 ml insulin was diluted with 3 ml of normal saline before each dose with estimated viability of 1 hour.

The blood sugar was tested prior to each feed. Short acting insulin dose was not given when blood sugar was below 100 mg⁄dl. The baby had few hypoglycemic episodes that were corrected by glucose infusions. There was no seizure episodes related to hypoglycemia. Continuous Glucose Monitoring Sensor (CGMS) was considered to monitor fluctuations in blood sugar, but lack of ample subcutaneous fat precluded the stability of the sensor’s needle. The aim of the therapy was to treat hyperglycemia while preventing hypoglycemia episodes. Blood glucose was kept in the range of 150–200 mg⁄dl.

At two months of age, the patient had gained weight (3.35 kg), had increased subcutaneous fat and was requiring a larger daily dose of long acting insulin (total dose of 2 units per day). The patient was discharged home at the age of two months with scheduled follow–up in 1 week.

The major obstacles in treating neonatal diabetes mellitus that we faced were:

• Difficulty in preparing very low dose insulin. Most of the manufacturers of commercially available insulin advise against any form of dilutions to prevent any possibility of dysfunction. We had no other choice.
• Difficulty with insulin administration in a very thin newborn with lack of subcutaneous fat tissue. ntramuscular insulin injection may also cause erratic insulin absorption
• Difficulty in predicting milk intake. Like any normal newborn, feeding may be variable. The patient experienced hypoglycemic episodes on days that he was not able to finish or tolerate his feeds.
• Consequences of multiple blood sticks to test blood sugar and frequent blood draws that could theoretically cause anemia. We have adhered to our hospital protocol to prevent this from occurring.
• Physical and psychological factors that affected the family members of the patient on daily diabetes management.

Neonatal diabetes mellitus (NDM) is an extremely rare presentation of diabetes. The National Institute of Health (NIH) estimates the incidence of NDM between 1 in 100,000 to 1 in 500,000 live births. [1] Varying by region.

An Italian study reported an incidence of 1 in 90,000 live births in Italy [2]. Since the condition is usually caused by a single gene mutation, it is expected to have a higher incidence in geographical regions with high rates of consanguinity, as was seen in our subject family.

Initially neonatal diabetes seemed divided in two types: Transient (TNDM) and Permanent (PNDM). This classification clearly depends on the duration and progression of the condition [3]. In almost 50% of the cases, NDM is transient disappearing in infancy with possibility of recurrence later on in life. In the other half, NDM is permanent.

NDM should be differentiated from other causes of hyperglycemia in the newborn including iatrogenic causes, stress and insulin resistance [4].

NDM should be differentiated also from type 1 diabetes mellitus (autoimmune) that may start at early infancy (as early as 6 months of age) [1]. Type 1 diabetes is almost always associated with positive immune markers for diabetes (Table).

Persistent hyperglycemia, insulin deficiency (low insulin and C–peptide levels) are common features in making the diagnosis. Lack of immune markers for type 1 diabetes may be deceiving for late onset presentation. The most important aspect of the confirming the diagnosis is molecular genetic testing. There are more than a dozen genes⁄loci associated with neonatal diabetes [5–9].

Some examples of the known mutations causing neonatal diabetes are: [5].

6q24, solute carrier family 2A2 (SLC2A2)

SLC 19 A2, eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3)

Pancreas transcription factor 1 subunit alpha (IPF1A)

Hepatocyte nuclear factor 1 homeobox B (HNF1B)

Forkhead box P 3 (FOXP3)

Zinc finger protein 57 (ZFP57)

The prevalence of these mutations can vary from one region to another worldwide [5,10] but KCNJII, ABCC8, GCK and IPF1 are the most commonly reported.

Genetic testing may play a very important role in transferring therapy from insulin to sulfonylurea since patients with certain mutations in the pancreatic ATP sensitive K+ channel proteins like the sulfonylurea receptor 1 (SUR1) and inward rectifier K+ channel Kir 6.2 (Kir 6.2) may respond well to sulfonylurea therapy [10–13] instead of insulin.

There are some syndromic forms of neonatal diabetes described like Berardinelli–Seip Syndrome [14], associated with insulin resistance and congenital lipodystrophy and Wolcott–Rallison Syndrome [15] associated with multiple epiphyseal dysplasia, osteopenia, mental retardation and hepatic and renal dysfunction.

• National Diabetes Information Clearinghouse (NDIC)
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• Babenko AP, Polak M, Cavé H, Busiah K, Czernichow P, Scharfmann R, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006; 355: 456-466.
• Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004; 350: 1838-1849.
• Clement JP 4th, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, et al. Association and stoichiometry of K(ATP) channel subunits. Neuron. 1997; 18: 827-838.
• Ellard S, Flanagan SE, Girard CA, Patch AM, Harries LW, Parrish A, et al. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet. 2007; 81: 375-382.
• Stanik J, Gasperikova D, Paskova M, Barak L, Javorkova J, Jancova E, et al. Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab. 2007; 92: 1276-1282.
• Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes. 2004; 53: 2713-2718.
• Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin B, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006; 355: 467-477.
• Rafiq M, Flanagan SE, Patch AM, Shields BM, Ellard S, Hattersley AT. Neonatal Diabetes International Collaborative Group. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care. 2008; 31: 204-209.
• Agarwal AK, Garg A. Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends Endocrinol Metab. 2003; 14: 214-221.
• Rubio-Cabezas O, Patch AM, Minton JA, Flanagan SE, Edghill EL, Hussain K, et al. Wolcott-Rallison syndrome is the most common genetic cause of permanent neonatal diabetes in consanguineous families. J Clin Endocrinol Metab. 2009; 94: 4162-4170.

Citation: Yafi M. A Case of Neonatal Diabetes Presentation, Diagnosis and Management. Austin J Pediatr. 2014;1(1): 1004. ISSN: 2381-8999

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Classification of Neonatal Diabetes

• First Online: 08 April 2023

Cite this chapter

• Elisa De Franco 3 &
• Matthew B. Johnson 3  

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Neonatal Diabetes Mellitus (NDM) is diagnosed in the first 6 months of life and is most likely to have a monogenic cause rather than being polygenic type 1 diabetes.

Before widespread genetic testing and the identification of the main genetic subtypes, NDM was classified based on disease progression and presence of additional syndromic features. Recent genetic discoveries have identified >30 genetic causes of NDM, mostly affecting genes involved in beta-cell development, function, and survival. A molecular diagnosis guides treatment and is now the gold standard for NDM disease classification.

This chapter discusses the clinical and genetic features of neonatal and early-onset diabetes, and how NDM classification helps management of the patients’ disease.

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De Franco, E., Johnson, M.B. (2023). Classification of Neonatal Diabetes. In: Rabbone, I., Iafusco, D. (eds) Neonatal and Early Onset Diabetes Mellitus. Springer, Cham. https://doi.org/10.1007/978-3-031-07008-2_4

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Study: Black/African American individuals have an increased risk for severe insulin-deficient diabetes

by Hannah Echols, University of Alabama at Birmingham

While diabetes patients are categorized into two groups, either type 1 or type 2, no two patients are the same. The simple categorization often does not portray the disease and its many presentations, especially within different populations. For this reason, diabetes researchers and clinicians have emphasized the importance of increasing the understanding of diabetes subtypes.

Researchers at the University of Alabama at Birmingham have conducted a cluster analysis of diabetes in the Deep South to understand how the disease, and its subtypes, are clustered among the diverse population. Results published in the Journal of Clinical Endocrinology and Metabolism showed that Black/African American individuals have an increased risk for severe insulin-deficient diabetes, a subtype of type 2 diabetes.

Those with SIDD typically are diagnosed at a younger age, are leaner and have worse blood sugar control, leading to higher A1c. Their beta cell function is impaired, making it harder to produce insulin, and they have a higher risk for complications such as a heart attack.

"Understanding that Black/African American individuals have an increased risk for SIDD has practical implications as it can help guide clinicians to more appropriate treatments for these individuals and hopefully improve outcomes, reduce complications and cut health care expenditures ," said Anath Shalev, M.D., the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Juvenile Diabetes Research in the UAB Division of Endocrinology, Diabetes and Metabolism in the Department of Medicine and the director of the UAB Comprehensive Diabetes Center.

Recent studies have defined new subgroups of adult-onset diabetes and their associations with disease progression and complications. However, the studies were focused primarily on Northern European or North American white/Caucasian populations.

The multidisciplinary team from the UAB Comprehensive Diabetes Center, the Hugh Kaul Precision Medicine Institute, and Division of Endocrinology, Diabetes and Metabolism wanted to determine whether similar clustering as in previous studies could be applied to diverse cohorts. They studied data from 89,875 patients with diabetes in the Deep South over a 10-year period.

"UAB is uniquely located in a region where the prevalence of diabetes is much higher than other areas of the United States and consists of a more diverse population," said Brian Lu, Ph.D., first author and researcher in the UAB Comprehensive Diabetes Center. "Our study shows that racial background strongly influences diabetes subtype distribution."

Results add to the growing literature and push for more research to define and better understand diabetes subtypes. The findings are an example of precision diabetes that can be used in practical, clinical settings .

"The more that we know about an individual's risks and specific subtype of diabetes, the more personalized we can make their care," said Matt Might, Ph.D., director of the Hugh Kaul Precision Medicine Institute. "This is another exciting discovery in precision diabetes."

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• v.2023; 2023
• PMC10468271

Management of Neonatal Diabetes due to a KCNJ11 Mutation with Automated Insulin Delivery System and Remote Patient Monitoring

Ming yeh lee.

1 Division of Pediatric Endocrinology, Stanford University School of Medicine, Stanford, CA, USA

Anna L. Gloyn

2 Stanford Diabetes Research Center, Stanford University School of Medicine, Stanford, CA, USA

David M. Maahs

Priya prahalad, associated data.

The data used to support the findings of this study are available from the corresponding author upon request.

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes. Management of hyperglycemia in neonates with subcutaneous insulin is challenging because of frequent feeding, variable quantity of milk intake with each feed, low insulin dose requirements, and high risk for hypoglycemia and associated complications in this population. We present a case of NDM in a proband initially presenting with focal seizures and diabetic ketoacidosis due to a pathologic mutation in the beta cell potassium ATP channel gene KCNJ11 c.679G > A (p.E227K). We describe the use of continuous glucose monitoring (CGM), insulin pump, automated insulin delivery system, and remote patient monitoring technologies to facilitate rapid and safe outpatient cross-titration from insulin to oral sulfonylurea. Our case highlights the safety and efficacy of these technologies for infants with diabetes, including improvements in glycemia, quality of life, and cost-effectiveness by shortening hospital stay.

1. Introduction

Neonatal diabetes mellitus (NDM) occurs in approximately 1 in 90,000 to 160,000 live births [ 1 ]. Genetic testing provides the diagnosis and guides clinical therapy. Mutations affecting the pancreatic beta cell potassium ATP channel genes ( KCNJ11 and ABCC8 ) are common in neonatal diabetes, and these patients can often be transitioned from insulin to oral sulfonylurea therapy [ 2 ]. In a healthy pancreatic beta cell, glucose enters via a glucose transporter, where it is metabolized, resulting in a change in the ratio between ADP and ATP which results in closure of ATP-dependent potassium (K ATP ) channels leading to membrane depolarization and activation of voltage-dependent calcium channels. The subsequent influx of calcium is the trigger for insulin release. Heterozygous activating mutations in the genes encoding for the two subunits of the K ATP channel ( KCNJ11 or ABCC8 ) result in an inability of ATP to lead to channel closure which prevents insulin secretion [ 2 ]. Sulfonylureas close the K ATP channel by an ATP-independent mechanism, allowing for insulin to be released from the beta cell [ 1 ]. Patients with this genetic etiology for their diabetes can be treated with oral sulfonylureas rather than insulin with improvements in both glycemia and quality of life (QoL) [ 3 – 5 ].

Management of NDM with subcutaneous insulin is challenging because of frequent feeding, variable quantity of milk intake with each feed, low insulin dose requirements, and high risk for hypoglycemia and associated complications in infants. Various technologies including continuous glucose monitors (CGMs), insulin pumps, automated insulin delivery (AID) systems, and remote patient monitoring (RPM) have improved glycemia and QoL for youth with type 1 diabetes [ 6 ]. These technologies are likely to improve NDM management although they have not been well studied nor have FDA approval for use in this population. CGMs have been utilized for glucose monitoring in neonates with conditions such as NDM and congenital hyperinsulinism [ 7 ]. CGMs are beneficial for alerting impending hypoglycemia, allowing caregivers to recognize and treat hypoglycemia in neonates, who otherwise have difficult to recognize hypoglycemia symptoms. Insulin pumps may benefit NDM management by (1) allowing precise delivery of small insulin doses compared to subcutaneous injections, (2) allowing flexibility of frequent insulin boluses for hyperglycemia correction or carbohydrate coverage without additional injections, and (3) minimizing the potential for stacking of insulin boluses, leading to hypoglycemia with the insulin-on-board feature [ 1 ].

AID systems combine a CGM, an insulin pump, and a dosing algorithm for insulin delivery. Guidelines from the International Society for Pediatric and Adolescent Diabetes and American Diabetes Association strongly recommend the use of AID systems for youth with diabetes, as these systems improve CGM time in range (TIR, glucose 70–180 mg/dL) [ 8 , 9 ]. Previously, AID systems have been used for the management of hyperglycemia in extremely preterm infants in the neonatal intensive care unit, demonstrating improved TIR and optimized nutritional intake without increasing the risk of hypoglycemia [ 10 ]. However, outpatient use of AID systems for management of NDM has not been reported. RPM allows flexible and timely interventions for youth with diabetes without requiring additional clinic visits [ 11 ]. Historically, titration from insulin to sulfonylurea therapy has occurred rapidly in an inpatient setting or more slowly in an outpatient setting. Our case demonstrates that early diagnosis of sulfonylurea-responsive NDM and incorporation of AID and close guidance of experienced pediatric endocrinologists led to safe, fast, and effective transition to sulfonylurea therapy and glycemic control in the outpatient setting, while improving patient and family's QoL.

2. Case Presentation

A 2-month-old female presented to the emergency department with left-sided focal seizures. She had no infectious symptoms and had been feeding and acting normally. She was born full term with history of small for gestational age (birth weight of 2205 g, 0.6 percentile). At 6 weeks of age, she had good catch up growth to 3459 g (1.58 percentile) and normal development. Her physical exam was normal with no dysmorphic features and no focal neurological deficits. Initial laboratory evaluation was notable for glucose of 604 mg/dL and mild diabetic ketoacidosis (DKA) with venous pH 7.28, beta-hydroxybutyrate 4.2 mmol/L, elevated hemoglobin A1c 8.5%, and low c-peptide 0.45 ng/ml. Head CT showed no acute intracranial abnormalities. Brain MRI was notable for foci of restricted diffusion in the bilateral frontal cerebral white matter, bilateral cerebellar white matter, and right putamen with surrounding signal abnormality. She was admitted to the pediatric intensive care unit for intravenous insulin and fluids based on the institutional DKA protocol and for seizure monitoring and treatment. She remained on broad-spectrum antibiotics until infectious workup was negative. Continuous electroencephalogram (EEG) demonstrated focal right temporal seizures that were associated with left facial and eyelid twitching. EEG also demonstrated focal slowing in the right hemisphere, which is a nonspecific indicator of cerebral dysfunction from a wide variety of potential etiologies. Pediatric neurology and radiology considered these findings most likely related to severe infantile hyperglycemic injury.

3. Treatment, Outcome, and Follow-Up

On day 2 of admission, DKA resolved and she transitioned from intravenous to subcutaneous insulin ( Figure 1 ). Genetic panel for monogenic diabetes was sent. Since her clinical presentation was highly suspicious for NDM and genetic testing was still pending, we initiated discharge planning for potential long-term insulin requirement. She was initiated on the Dexcom G6 (Dexcom, San Diego, CA) CGM for glucose monitoring and family received teaching for diabetes management. While insulin pump and AID system were recognized as tools for aiding glycemia, barriers to inpatient initiation of technologies included lack of hospital policy and lack of familiarity and comfort from primary providers and nursing staff. Thus, initiation of insulin pump and AID system was deferred until an outpatient clinic visit.

Timeline of clinical events.

Subcutaneous insulin doses were initiated during admission using basal-bolus strategy with U100 Lantus once daily and diluted U10 Humalog for hyperglycemia correction every 4 hours. Doses were titrated daily during the first week of diagnosis, to total daily insulin dose of 5 units (1.4 units/kg/day). Blood glucose target was set at 200 mg/dL due to the risk for complications from hypoglycemia. Glycemia was poor during the initial week on subcutaneous insulin regimen, with mean glucose 300 mg/dL, standard deviation 59 mg/dL, CGM TIR (glucose 70-180 mg/dl) 4%, time in hyperglycemia (glucose above 180 mg/dL) 96%, and no hypoglycemia (glucose less than 70 mg/dL) ( Figure 2 ). Challenges to management include limitation of subcutaneous insulin dose increments, insulin dose injection volume, risk of hypoglycemia, frequency of feeding, and variable amount of feeding due to changing mental status while titrating antiepileptics. Seizure control required 4 antiepileptics.

CGM glucose pattern summary data during various periods of treatment.

By day 9 after diagnosis, patient returned to baseline mental status, was feeding well, and was seizure free on a stable regimen of antiepileptics. She was discharged directly to the diabetes clinic for initiation of the t:slim X2 insulin pump (Tandem, San Diego, CA) with Control-IQ technology for AID. The pump was loaded with dilute U10 Humalog, with basal rate set to 0.1 unit/hour, carbohydrate ratio of 1 unit per 60 g carbohydrates, and correction factor of 1 unit to glucose of 400 mg/dL. The pump was set to “exercise mode” of control-IQ to enable higher glucose target. CGM and insulin data are shared with the diabetes team via Dexcom Clarity (Dexcom, San Diego, CA) and t:connect (Tandem, San Diego, CA) web portals, respectively, for RPM in between clinic visits. Glycemia was improved on AID compared with multiple daily injection insulin. Her mean glucose was 211 ± 43 mg/dL, TIR 23%, hyperglycemia 77%, and no hypoglycemia ( Figure 2 ).

Week 2 after presentation, genetic testing identified a KCNJ11 c.679G > A (p.E227K) heterozygous mutation, a pathologic variant in the gene encoding for potassium ATP channel in pancreatic beta cells [ 1 ]. Reflex genetic testing on the patient's parents were negative for the same pathologic variant, indicating that this was a de novo mutation. Rare pathogenic mutations in KCNJ11 are a cause of multiple disorders of insulin secretion with the direction of effect depending on whether mutations result in a loss or gain of function. Heterozygous activating mutations can cause several varieties of NDM, including both permanent and transient forms, with the functional severity of the mutation influencing the clinical presentation [ 2 ]. Patients with KCNJ11 activating mutations are typically responsive to treatment with oral sulfonylureas with improvements in both glycemia and QoL due to the ease of administrating oral medication versus insulin injections multiple times daily [ 1 , 3 – 5 ]. Several studies indicate that commencing treatment at the earliest opportunity may also improve neurodevelopmental outcomes in sulfonylurea-responsive patients [ 1 ].

Day 18 after diagnosis, we initiated cross-titration from insulin to glyburide, an oral sulfonylurea, based on a published protocol [ 1 ]. Typically, outpatient cross-titration of oral sulfonylurea is titrated weekly due to the risk of hypoglycemia when insulin requirement decreases. However, we were able to safely and rapidly achieve outpatient cross-titration using the AID system coupled with RPM ( Figure 3 ). The AID system minimizes risk of hypoglycemia by suspending insulin delivery in response to hypoglycemia or anticipated hypoglycemia. Asynchronous RPM with pediatric endocrinologist reviewing CGM and AIDs data every 2-3 days facilitated frequent outpatient dose adjustments. By day 9 of cross-titration, glyburide was titrated to 0.45 mg/kg/day and insulin was weaned off. This was a similar timeline as inpatient cross-titration, and much more rapid compared to outpatient cross-titration [ 1 ]. During cross-titration, glycemia continued to improve (mean glucose 169 ± 47 mg/dL, TIR 58%, hyperglycemia 41%, and hypoglycemia <1%). Review of AID data showed that insulin delivery suspended appropriately in anticipation of hypoglycemia ( Figure 4 ). On glyburide monotherapy, glycemia was achieved (mean glucose 130 ± 38 mg/dL, TIR 86%, hyperglycemia 10%, and hypoglycemia <4%). Week 5 after diagnosis, she had intermittent preprandial hypoglycemia suggestive of clinical remission from diabetes. Glyburide was weaned off with subsequent normoglycemia (mean glucose 110 ± 26 mg/dL, CGM 95%, hyperglycemia 1%, and hypoglycemia <4%) ( Figure 2 ). Overall, this clinical course is consistent with an activating mutation in KCNJ11 leading to transient NDM (TNDM). A large proportion of TNDM cases subsequently relapse and will require insulin therapy, most often during adolescence [ 1 ]. Thus, it remains important to monitor for signs and symptoms of hyperglycemia and periodically monitor hemoglobin A1c even if she is off insulin and sulfonylurea.

Timeline of insulin to glyburide cross-titration. Glyburide dose was quickly up-titrated as an outpatient every 2-3 days to maximal effect over 1 week. Insulin was safely weaned off 9 days after initiation of glyburide.

Representative CGM and insulin pump data for 24 hours during glyburide cross-titration. Two dashed lines mark anticipated hypoglycemia and appropriate suspension of insulin delivery from the pump.

4. Discussion

Some activating mutations in KCNJ11 have been associated with developmental delay, epilepsy, and neonatal diabetes (DEND) and intermediate DEND (iDEND) syndrome. In addition to the pancreatic islet, KCNJ11 is also expressed in neurons and skeletal muscles; thus, altered activity of K ATP channels in these tissues may explain the neurodevelopmental features [ 2 ]. The KCNJ11 p.E227K mutation has been reported in patients with a range of diabetes presentation including neonatal and later-onset phenotypes [ 12 – 14 ]. It has been previously described in a patient with TNDM, axial hypotonia during infancy, and moderate neurodevelopmental delay in language and mathematical reasoning during childhood [ 15 ]. However, this mutation has not been associated with seizures. In children with type 1 diabetes, long-term changes in brain structure and cognitive function have been associated with hyperglycemia [ 16 ]. Thus, our patient's initial seizures may have been provoked by hyperglycemic brain injury. She has been followed by pediatric neurology and developmental-behavioral pediatrics with no concerns about development, no more clinical seizures, and a normal EEG while weaning antiepileptics. She will continue to follow with neurology for neurodevelopmental monitoring. Given her history of seizures, it is important to closely manage her blood glucoses to avoid further neurologic insult from hyperglycemia or hypoglycemia.

In summary, our experience demonstrates that management of infants with NDM using the AID system and RPM under close guidance of experienced pediatric endocrinologists can lead to safe and effective glycemic control and at home transition to sulfonylurea therapy. Benefits of these technologies include improved TIR by minimizing hyperglycemia and hypoglycemia and improved QoL for the family. The strategy of using AID systems coupled with RPM further allows frequent outpatient medication titration, thus reducing the length of hospital stay and cost. We advocate that all children should be allowed to use these technologies inpatient and outpatient when proper supervision by experienced medical providers is available. Our report has broad implications as hospital policies and infrastructure need to be reviewed and updated regularly to prevent hindering optimal patient care through application of novel technologies.

Acknowledgments

The authors would like to thank the patient and her family. They thank Jeannine Leverenz, the certified diabetes care and education specialists, and pediatric endocrinologists at the Division of Pediatric Endocrinology and Diabetes at Stanford for their expertise in diabetes technologies, patient education, and clinical care. They thank Dr. Siri Greeley and the Monogenic Diabetes Team at the University of Chicago Kovler Diabetes Center for discussions on sulfonylurea transfer. They thank Dr. Catarina Limbert for discussions on neurodevelopmental phenotype of KCNJ11 p.E227K mutation. MYL is supported by the Elizabeth and Russell Siegelman Postdoctoral Fellowship award by the Stanford Maternal & Child Health Research Institute (MCHRI) and the Ruth L. Kirschstein National Research Service Award (NRSA) T32 Training Program in Diabetes, Endocrinology, and Metabolism at Stanford (DK007217-46). ALG, DMM, and PP are supported by the National Institute of Diabetes and Digestive and Kidney Diseases under Grant no. P30DK113358.

Data Availability

Additional points.

(i) Availability of rapid genetic testing allows possibility of early transition from insulin to sulfonylurea therapy for patients with neonatal diabetes caused by KCNJ11 and ABCC8 mutations. (ii) Glycemic management of neonates with diabetes is challenging due to limitations in subcutaneous insulin dose increments, insulin dose injection volume, high risk of hypoglycemia, high frequency of feeding, and variable amount of feeding. (iii) Management of neonatal diabetes using AID systems and RPM under close guidance of experienced pediatric endocrinologists can lead to safe and effective glycemia by minimizing both hyperglycemia and hypoglycemia.

The authors have obtained written consent from the parent of the patient.

Conflicts of Interest

ALG's spouse works for Genentech and holds stock options in Roche. The authors declare that there are no conflicts of interest.

Authors' Contributions

MYL and PP conducted data analysis and wrote the initial manuscript. ALG and DMM provided critical revisions to the manuscript. All authors have approved the final manuscript prior to submission.