Causes of NDM

PNDM and TNDM are inherited genetically from the mother or father of the infant. Different genetic inheritance or genetic mutations can lead to different diagnosis of NDM (Permanent or Transient Neonatal Diabetes Mellitus). The following are different types of inheritance or mutations:

- "Autosomal Dominant": Every cell has two copies of each gene-one gen coming from the mother and one coming from the father. Autosomal dominant inheritance pattern is defined as a mutation that occurs in only one copy of the gene. A parent with the mutation can pass on a copy of the gene and a parent with the mutation can pass on a copy of their working gene (or a copy of their damaged gene). In an autosomal dominant inheritance, a child who has a parent with the mutation has a 50% possibility of inheriting the mutation.

- "Autosomal Recessive" -Autosomal recessive-Generally, every cells have two copies of each gene-one gene is inherited from the mother and one gene is inherited from the father. Autosomal recessive inheritance pattern is defined as a mutation present in both copies if the gene in order for a person to be affected and each parent much pass on a mutated gene for a child to be affected. However, if an infant or child has only one copy, he or she are a carrier of the mutation. If moth parents are carriers of the recessive gene mutation, each child have a 25% chance of inheriting the gene.

- "Spontaneous": A new mutation or change occurs within the gene.

- "X-linked:" When a trait or disease happens in a person who has inherited a mutated gene on the X chromosome (one of the sex chromosome).

Prevention: There are no current prevention methods, because TNDM or PNDM are inherited genetically.

Sedentary lifestyle increases the likelihood of development of insulin resistance. It has been estimated that each 500 kcal/week increment in physical activity related energy expenditure, reduces the lifetime risk of type 2 diabetes by 9%. A different study found that vigorous exercise at least once a week reduced the risk of type 2 diabetes in women by 33%.

Metabolic syndrome affects 60% of the U.S. population older than age 50. With respect to that demographic, the percentage of women having the syndrome is higher than that of men. The age dependency of the syndrome's prevalence is seen in most populations around the world.

Several associated risk factors include the following:

- Genetic factors (inherited component):

- Family history of type 2 diabetes

- Insulin receptor mutations (Donohue syndrome)

- LMNA mutations (familial partial lipodystrophy)

- Cultural variables, such as diet varying with race and class; factors related to stress, socio-economic status and history have been shown to activate the stress response, which increases the production of glucose and insulin resistance, as well as inhibiting pancreatic function and thus might be of importance, although it is not fully corroborated by the scientific evidence.

- Particular physiological conditions and environmental factors:

- Age 40–45 years or older

- Obesity

- The tendency to store fat preferentially in the abdomen (also known as "abdominal obesity)", as opposed to storing it in hips and thighs

- Sedentary lifestyle, lack of physical exercise

- Hypertension

- High triglyceride level (hypertriglyceridemia)

- Low level of high-density lipoprotein (also known as HDL cholesterol or "good cholesterol")

- Prediabetes, blood glucose levels have been too high in the past, i.e. the patient's body has previously shown slight problems with its production and usage of insulin ("previous evidence of impaired glucose homeostasis")

- Having developed gestational diabetes during past pregnancies

- Giving birth to a baby weighing more than 9 pounds (a bit over 4 kilograms)

- Pathology:

- Obesity and overweight (BMI > 25)

- Metabolic syndrome (hyperlipidemia + HDL cholesterol level 2.82 mmol/L), hypertension (> 140/90 mmHg), or arteriosclerosis

- Liver pathologies

- Infection (Hepatitis C)

- Hemochromatosis

- Gastroparesis

- Polycystic ovary syndrome (PCOS)

- Hypercortisolism (e.g., Cushing's syndrome, glucocorticoid therapy)

- Medications (e.g., glucosamine, rifampicin, isoniazid, olanzapine, risperidone, progestogens, glucocorticoids, methadone, many antiretrovirals)

The outcome for infants or adults with NDM have different outcomes among carriers of the disease. Among affected babies, some have PNDM while others have relapse of their diabetes and other patients may experience permanent remission. Diabetes may reoccur in the patient's childhood or adulthood. It was estimated that neonatal diabetes mellitus will be TNDM in about 50% are half of the cases.

During the Neonatal stage, the prognosis is determined by the severity of the disease (dehydration and acidosis), also based on how rapidly the disase is diagnosed and treated. Associated abnormalities (e.g. irregular growth in the womb or enlarged tongue) can effect a person's prognosis. The long-term prognosis depends on the person's metabolic control, which effects the presence and complications of diabetes complications. The prognosis can be confirmed with genetic analysis to find the genetic cause of the disease. WIth proper management, the prognosis for overall health and normal brain development is normally good. It is highly advised people living with NDM seek prognosis from their health care provider.

Lipodystrophic disorders in general are associated with metabolic syndrome. Both genetic (e.g., Berardinelli-Seip congenital lipodystrophy, Dunnigan familial partial lipodystrophy) and acquired (e.g., HIV-related lipodystrophy in patients treated with highly active antiretroviral therapy) forms of lipodystrophy may give rise to severe insulin resistance and many of metabolic syndrome's components.

This not known with certainty but is estimated to be about one per million. It appears to be more common in females than males.

Lifestyle factors are important to the development of type 2 diabetes, including obesity and being overweight (defined by a body mass index of greater than 25), lack of physical activity, poor diet, stress, and urbanization. Excess body fat is associated with 30% of cases in those of Chinese and Japanese descent, 60–80% of cases in those of European and African descent, and 100% of cases in Pima Indians and Pacific Islanders. Among those who are not obese, a high waist–hip ratio is often present. Smoking appears to increase the risk of type 2 diabetes mellitus.

Dietary factors also influence the risk of developing type 2 diabetes. Consumption of sugar-sweetened drinks in excess is associated with an increased risk. The type of fats in the diet are important, with saturated fats and trans fatty acids increasing the risk, and polyunsaturated and monounsaturated fat decreasing the risk. Eating a lot of white rice appears to play a role in increasing risk. A lack of exercise is believed to cause 7% of cases. Persistent organic pollutants may play a role.

It is estimated that between 6-50% of all persons, depending on population, diagnosed with type 2 diabetes might actually have LADA. This number accounts for an estimated 5–10% of the total diabetes population in the U.S. or, as many as 3.5 million persons with LADA. People with LADA typically have a normal BMI or may be underweight due to weight loss prior to diagnosis. Some people with LADA, however, may be overweight to mildly obese.

Contrary to popular belief, some people having LADA do carry a family history of type 2 diabetes.

In some forms of MODY, standard treatment is appropriate, though exceptions occur:

- In MODY2, oral agents are relatively ineffective and insulin is unnecessary.

- In MODY1 and MODY3, insulin may be more effective than drugs to increase insulin sensitivity.

- Sulfonylureas are effective in the K channel forms of neonatal-onset diabetes. The mouse model of MODY diabetes suggested that the reduced clearance of sulfonylureas stands behind their therapeutic success in human MODY patients, but Urbanova et al. found that human MODY patients respond differently to the mouse model and that there was no consistent decrease in the clearance of sulfonylureas in randomly selected HNF1A-MODY and HNF4A-MODY patients.

Since hyperinsulinemia and obesity are so closely linked it is hard to determine whether hyperinsulinemia causes obesity or obesity causes hyperinsulinemia, or both.

Obesity is characterized by an excess of adipose tissue – insulin increases the synthesis of fatty acids from glucose, facilitates the entry of glucose into adipocytes and inhibits breakdown of fat in adipocytes.

On the other hand, adipose tissue is known to secrete various metabolites, hormones and cytokines that may play a role in causing hyperinsulinemia. Specifically cytokines secreted by adipose tissue directly affect the insulin signalling cascade, and thus insulin secretion. Adiponectins are cytokines that are inversely related to percent body fat; that is people with a low body fat will have higher concentrations of adiponectins where as people with high body fat will have lower concentrations of adiponectins. Weyer "et al." (2011) reported that hyperinsulinemia is strongly associated with low adiponectin concentrations in obese people, though whether low adiponectin has a causal role in hyperinsulinemia remains to be established.

- May lead to hypoglycemia or diabetes

- Increased risk of PCOS

- Increased synthesis of VLDL (hypertriglyceridemia)

- Hypertension (insulin increases sodium retention by the renal tubules)

- Coronary Artery Disease (increased insulin damages endothelial cells)

- Increased risk of cardiovascular disease

- Weight gain and lethargy (possibly connected to an underactive thyroid)

Classical risk factors for developing gestational diabetes are:

- Polycystic Ovary Syndrome

- A previous diagnosis of gestational diabetes or prediabetes, impaired glucose tolerance, or impaired fasting glycaemia

- A family history revealing a first-degree relative with type 2 diabetes

- Maternal age – a woman's risk factor increases as she gets older (especially for women over 35 years of age).

- Ethnicity (those with higher risk factors include African-Americans, Afro-Caribbeans, Native Americans, Hispanics, Pacific Islanders, and people originating from South Asia)

- Being overweight, obese or severely obese increases the risk by a factor 2.1, 3.6 and 8.6, respectively.

- A previous pregnancy which resulted in a child with a macrosomia (high birth weight: >90th centile or >4000 g (8 lbs 12.8 oz))

- Previous poor obstetric history

- Other genetic risk factors: There are at least 10 genes where certain polymorphism are associated with an increased risk of gestational diabetes, most notably TCF7L2.

In addition to this, statistics show a double risk of GDM in smokers. Polycystic ovarian syndrome is also a risk factor, although relevant evidence remains controversial. Some studies have looked at more controversial potential risk factors, such as short stature.

About 40–60% of women with GDM have no demonstrable risk factor; for this reason many advocate to screen all women. Typically, women with GDM exhibit no symptoms (another reason for universal screening), but some women may demonstrate increased thirst, increased urination, fatigue, nausea and vomiting, bladder infection, yeast infections and blurred vision.

The condition is transmitted as an autosomal recessive trait, and often affects children of consanguineous parents. The physical findings and symptoms vary greatly among each individual.

Genetic diseases are determined by two genes, one from the mother and one from the father. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If one of the inherited genes is normal, while the other is for the disease, the person will only be a carrier and will not display any symptoms.

The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent.

Researchers have determined that the Rabson–Mendenhall syndrome is caused by mutations of the insulin receptor gene. The insulin receptor gene is located on the short arm (p) of chromosome 19. Mutations of the insulin-receptor gene lead to an alteration of structure or reduced number of insulin receptors. This results in reduced binding of insulin, and may also lead to abnormalities in the post-receptor pathway.

Individuals with Rabson-Mendenall syndrome will need ways to compensate for their insulin resistance, and may do this by increasing insulin secretion. This can lead to excessive insulin levels in the blood (hyperinsulinemia), which can be responsible for multiple symptoms. Definitive genotype–phenotype correlation for insulin receptor defects is difficult to establish primarily due to the rarity of these syndromes. However, researchers believe more severe phenotype changes are due to a mutation in the alpha subunit of the receptor.

Breast feeding is good for the child even with a mother with diabetes mellitus. Some women wonder whether breast feeding is recommended after they have been diagnosed with diabetes mellitus. Breast feeding is recommended for most babies, including when mothers may be diabetic. In fact, the child’s risk for developing type 2 diabetes mellitus later in life may be lower if the baby was breast-fed. It also helps the child to maintain a healthy body weight during infancy. However, the breastmilk of mothers with diabetes has been demonstrated to have a different composition than that of non-diabetic mothers, containing elevated levels of glucose and insulin and decreased polyunsaturated fatty acids. Although benefits of breast-feeding for the children of diabetic mothers have been documented, ingestion of diabetic breast milk has also been linked to delayed language development on a dose-dependent basis.

AGL with autoimmune origin is responsible for about 25% of all AGL reports. Those with autoimmune origin stems from other autoimmune diseases, most commonly with juvenile dermatomyositis and autoimmune hepatitis, but also occurs with rheumatoid arthritis, systemic lupus erythematous, and Sjogren syndrome.

The American College of Endocrinology (ACE) and the American Association of Clinical Endocrinologists (AACE) have developed "lifestyle intervention" guidelines for preventing the onset of type 2 diabetes:

- Healthy meals (a diet with no saturated and trans fats, sugars, and refined carbohydrates, as well as limited the intake of sodium and total calories)

- Physical exercise (30–45 minutes of cardio vascular exercise per day, five days a week)

- Reducing weight by as little as 5–10 percent may have a significant impact on overall health

People with diabetes show an increased rate of urinary tract infection. The reason is bladder dysfunction that is more common in diabetics than in non-diabetics due to diabetic nephropathy. When present, nephropathy can cause a decrease in bladder sensation, which in turn, can cause increased residual urine, a risk factor for urinary tract infections.

The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients:

- Mild to moderate hyperglycemia (typically 130–250 mg/dl, or 7–14 mmol/l) discovered before 30 years of age. However, anyone under 50 can develop MODY.

- A first-degree relative with a similar degree of diabetes.

- Absence of positive antibodies or other autoimmunity (e.g., thyroiditis) in patient and family. However, Urbanova et al. found that about one quarter of Central European MODY patients are positive for islet cell autoantibodies (GADA and IA2A). Their expression is transient but highly prevalent. The autoantibodies were found in patients with delayed diabetes onset, and in times of insufficient diabetes control. The islet cell autoantibodies are absent in MODY in at least some populations (Japanese, Britons).

- Persistence of a low insulin requirement (e.g., less than 0.5 u/kg/day) past the usual "honeymoon" period.

- Absence of obesity (although overweight or obese people can get MODY) or other problems associated with type 2 diabetes or metabolic syndrome (e.g., hypertension, hyperlipidemia, polycystic ovary syndrome).

- Insulin resistance very rarely happens.

- Cystic kidney disease in patient or close relatives.

- Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before six months of age.

- Liver adenoma or hepatocellular carcinoma in MODY type 3

- Renal cysts, rudimentary or bicornuate uterus, vaginal aplasia, absence of the vas deferens, epidymal cysts in MODY type 5

The diagnosis of MODY is confirmed by specific gene testing available through commercial laboratories.

The development of type 2 diabetes is caused by a combination of lifestyle and genetic factors. While some of these factors are under personal control, such as diet and obesity, other factors are not, such as increasing age, female gender, and genetics. A lack of sleep has been linked to type 2 diabetes. This is believed to act through its effect on metabolism. The nutritional status of a mother during fetal development may also play a role, with one proposed mechanism being that of altered DNA methylation. The intestinal bacteriæ Prevotella copri and Bacteroides vulgatus have been connected with type 2 diabetes.

About 25% of previously reported AGL is associated with panniculitis. Panniculitis is an inflammatory nodules of the subcutaneous fat, and in this type of AGL, adipose destruction originates locally at the infection or inflammation site and develops into generalized lipodystrophy.

At present, there is no international standard classification of diabetes in dogs. Commonly used terms are:

- Insulin deficiency diabetes or primary diabetes, which refers to the destruction of the beta cells of the pancreas and their inability to produce insulin.

- Insulin resistance diabetes or secondary diabetes, which describes the resistance to insulin caused by other medical conditions or by hormonal drugs.

While the occurrence of beta cell destruction is known, all of the processes behind it are not. Canine primary diabetes mirrors Type 1 human diabetes in the inability to produce insulin and the need for exogenous replacement of it, but the target of canine diabetes autoantibodies has yet to be identified. Breed and treatment studies have been able to provide some evidence of a genetic connection. Studies have furnished evidence that canine diabetes has a seasonal connection not unlike its human Type 1 diabetes counterpart, and a "lifestyle" factor, with pancreatitis being a clear cause. This evidence suggests that the disease in dogs has some environmental and dietary factors involved.

Secondary diabetes may be caused by use of steroid medications, the hormones of estrus, acromegaly, (spaying can resolve the diabetes), pregnancy, or other medical conditions such as Cushing's disease. In such cases, it may be possible to treat the primary medical problem and revert the animal to non-diabetic status. Returning to non-diabetic status depends on the amount of damage the pancreatic insulin-producing beta cells have sustained.

It happens rarely, but it is possible for a pancreatitis attack to activate the endocrine portion of the organ back into being capable of producing insulin once again in dogs. It is possible for acute pancreatitis to cause a temporary, or transient diabetes, most likely due to damage to the endocrine portion's beta cells. Insulin resistance that can follow a pancreatitis attack may last for some time thereafter. Pancreatitis can damage the endocrine pancreas to the point where the diabetes is permanent.

Possible causes include:

- Neoplasm

- Pancreatic cancer

- Polycystic ovary syndrome (PCOS)

- Trans fats

Sexual dysfunction in diabetics is often a result of physical factors such as nerve damage and/or poor circulation, and psychological factors such as stress and/or depression caused by the demands of the disease.

GDM poses a risk to mother and child. This risk is largely related to uncontrolled high blood glucose levels and its consequences. The risk increases with higher blood glucose levels. Treatment resulting in better control of these levels can reduce some of the risks of GDM considerably.

The two main risks GDM imposes on the baby are growth abnormalities and chemical imbalances after birth, which may require admission to a neonatal intensive care unit. Infants born to mothers with GDM are at risk of being both large for gestational age (macrosomic) in unmanaged GDM, and small for gestational age and Intrauterine growth retardation in managed GDM. Macrosomia in turn increases the risk of instrumental deliveries (e.g. forceps, ventouse and caesarean section) or problems during vaginal delivery (such as shoulder dystocia). Macrosomia may affect 12% of normal women compared to 20% of women with GDM. However, the evidence for each of these complications is not equally strong; in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study for example, there was an increased risk for babies to be large but not small for gestational age in women with uncontrolled GDM. Research into complications for GDM is difficult because of the many confounding factors (such as obesity). Labelling a woman as having GDM may in itself increase the risk of having an unnecessary caesarean section.

Neonates born from women with consistently high blood sugar levels are also at an increased risk of low blood glucose (hypoglycemia), jaundice, high red blood cell mass (polycythemia) and low blood calcium (hypocalcemia) and magnesium (hypomagnesemia). Untreated GDM also interferes with maturation, causing dysmature babies prone to respiratory distress syndrome due to incomplete lung maturation and impaired surfactant synthesis.

Unlike pre-gestational diabetes, gestational diabetes has not been clearly shown to be an independent risk factor for birth defects. Birth defects usually originate sometime during the first trimester (before the 13th week) of pregnancy, whereas GDM gradually develops and is least pronounced during the first and early second trimester. Studies have shown that the offspring of women with GDM are at a higher risk for congenital malformations. A large case-control study found that gestational diabetes was linked with a limited group of birth defects, and that this association was generally limited to women with a higher body mass index (≥ 25 kg/m²). It is difficult to make sure that this is not partially due to the inclusion of women with pre-existent type 2 diabetes who were not diagnosed before pregnancy.

Because of conflicting studies, it is unclear at the moment whether women with GDM have a higher risk of preeclampsia. In the HAPO study, the risk of preeclampsia was between 13% and 37% higher, although not all possible confounding factors were corrected.

The risks of maternal diabetes to the developing fetus include miscarriage, growth restriction, growth acceleration, fetal obesity (macrosomia), mild neurological deficits, polyhydramnios and birth defects. A hyperglycemic maternal environment has also been associated with neonates that are at greater risk for development of negative health outcomes such as future obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome.

Mild neurological and cognitive deficits in offspring — including increased symptoms of ADHD, impaired fine and gross motor skills, and impaired explicit memory performance — have been linked to pregestational type 1 diabetes and gestational diabetes. Prenatal iron deficiency has been suggested as a possible mechanism for these problems.

Birth defects are not currently an identified risk for the child of women with gestational diabetes, since those primarily occur in the latter part of pregnancy, where vital organs already have taken their most essential shape.

Having diabetes type I or II prior to pregnancy has a 2- to 3-fold increase in risk of birth defects. The cause is, e.g., oxidative stress, by activating protein kinase C and lead to apoptosis of some cells.