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%.

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)

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)

Chronic hyperglycemia that persists even in fasting states is most commonly caused by diabetes mellitus. In fact, chronic hyperglycemia is the defining characteristic of the disease. Intermittent hyperglycemia may be present in prediabetic states. Acute episodes of hyperglycemia without an obvious cause may indicate developing diabetes or a predisposition to the disorder.

In diabetes mellitus, hyperglycemia is usually caused by low insulin levels (Diabetes mellitus type 1) and/or by resistance to insulin at the cellular level (Diabetes mellitus type 2), depending on the type and state of the disease. Low insulin levels and/or insulin resistance prevent the body from converting glucose into glycogen (a starch-like source of energy stored mostly in the liver), which in turn makes it difficult or impossible to remove excess glucose from the blood. With normal glucose levels, the total amount of glucose in the blood at any given moment is only enough to provide energy to the body for 20–30 minutes, and so glucose levels must be precisely maintained by the body's internal control mechanisms. When the mechanisms fail in a way that allows glucose to rise to abnormal levels, hyperglycemia is the result.

Ketoacidosis may be the first symptom of immune-mediated diabetes, particularly in children and adolescents. Also, patients with immune-mediated diabetes, can change from modest fasting hyperglycemia to severe hyperglycemia and even ketoacidosis as a result of stress or an infection.

Diabetic hypoglycemia can occur in any person with diabetes who takes any medicine to lower their blood glucose, but severe hypoglycemia occurs most often in people with type 1 diabetes who must take insulin for survival. In type 1 diabetes, iatrogenic hypoglycemia is more appropriately viewed as the result of the interplay of insulin excess and compromised glucose counterregulation rather than as absolute or relative insulin excess alone. Hypoglycemia can also be caused by sulfonylureas in people with type 2 diabetes, although it is far less common because glucose counterregulation generally remains intact in people with type 2 diabetes. Severe hypoglycemia rarely, if ever, occurs in people with diabetes treated only with diet, exercise, or insulin sensitizers.

For people with insulin-requiring diabetes, hypoglycemia is one of the recurrent hazards of treatment. It limits the achievability of normal glucoses with current treatment methods. Hypoglycemia is a true medical emergency, which requires prompt recognition and treatment to prevent organ and brain damage.

A 1988 study over 41 months found that improved glucose control led to initial "worsening of complications" but was not followed by the expected improvement in complications. In 1993 it was discovered that the serum of diabetics with neuropathy is toxic to nerves, even if its blood sugar content is normal.

Research from 1995 also challenged the theory of hyperglycemia as the cause of diabetic complications. The fact that 40% of diabetics who carefully controlled their blood sugar nevertheless developed neuropathy made clear other factors were involved.

In a 2013 meta-analysis of 6 randomized controlled trials involving 27,654 patients, tight blood glucose control reduced the risk for some macrovascular and microvascular events but without effect on all-cause mortality and cardiovascular mortality.

Certain medications increase the risk of hyperglycemia, including corticosteroids, octreotide, beta blockers, epinephrine, thiazide diuretics, niacin, pentamidine, protease inhibitors, L-asparaginase, and some antipsychotic agents. The acute administration of stimulants such as amphetamine typically produces hyperglycemia; chronic use, however, produces hypoglycemia. Some of the newer psychotropic medications, such as Zyprexa (Olanzapine) and Cymbalta (Duloxetine), can also cause significant hyperglycemia.

Thiazides are used to treat type 2 diabetes but it also causes severe hyperglycemia.

Research from 2007 suggested that in type 1 diabetics, the continuing autoimmune disease which initially destroyed the beta cells of the pancreas may also cause retinopathy, neuropathy, and nephropathy.

In 2008 it was even suggested to treat retinopathy with drugs to suppress the abnormal immune response rather than by blood sugar control.

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

Hypoglycemia due to endogenous insulin can be congenital or acquired, apparent in the newborn period, or many years later. The hypoglycemia can be severe and life-threatening or a minor, occasional nuisance. By far the most common type of severe but transient hyperinsulinemic hypoglycemia occurs accidentally in persons with type 1 diabetes who take insulin.

- Hypoglycemia due to endogenous insulin

- Congenital hyperinsulinism

- Transient neonatal hyperinsulinism (mechanism not known)

- Focal hyperinsulinism (K channel disorders)

- Paternal SUR1 mutation with clonal loss of heterozygosity of 11p15

- Paternal Kir6.2 mutation with clonal loss of heterozygosity of 11p15

- Diffuse hyperinsulinism

- K channel disorders

- SUR1 mutations

- Kir6.2 mutations

- Glucokinase gain-of-function mutations

- Hyperammonemic hyperinsulinism (glutamate dehydrogenase gain-of-function mutations)

- Short chain acyl coenzyme A dehydrogenase deficiency

- Carbohydrate-deficient glycoprotein syndrome (Jaeken's Disease)

- Beckwith-Wiedemann syndrome(suspected due to hyperinsulinism but pathophysiology uncertain: 11p15 mutation or IGF2 excess)

- Acquired forms of hyperinsulinism

- Insulinomas (insulin-secreting tumors)

- Islet cell adenoma or adenomatosis

- Islet cell carcinoma

- Adult nesidioblastosis

- Autoimmune insulin syndrome

- Noninsulinoma pancreatogenous hypoglycemia

- Reactive hypoglycemia (also see idiopathic postprandial syndrome)

- Gastric dumping syndrome

- Drug induced hyperinsulinism

- Sulfonylurea

- Aspirin

- Pentamidine

- Quinine

- Disopyramide

- Bordetella pertussis vaccine or infection

- D-chiro-inositol and myo-inositol

- Hypoglycemia due to exogenous (injected) insulin

- Insulin self-injected for treatment of diabetes (i.e., diabetic hypoglycemia)

- Insulin self-injected surreptitiously (e.g., Munchausen syndrome)

- Insulin self-injected in a suicide attempt or successful suicide

- Various forms of diagnostic challenge or "tolerance tests"

- Insulin tolerance test for pituitary or adrenergic response assessment

- Protein challenge

- Leucine challenge

- Tolbutamide challenge

- Insulin potentiation therapy

- Insulin-induced coma for depression treatment

Although one expects hypoglycemic episodes to be accompanied by the typical symptoms (e.g., tremor, sweating, palpitations, etc.), this is not always the case. When hypoglycemia occurs in the absence of such symptoms it is called "hypoglycemic unawareness". Especially in people with long-standing type 1 diabetes and those who attempt to maintain glucose levels which are closer to normal, hypoglycemic unawareness is common.

In patients with type 1 diabetes mellitus, as plasma glucose levels fall, insulin levels do not decrease - they are simply a passive reflection of the absorption of exogenous insulin. Also, glucagon levels do not increase. Therefore, the first and second defenses against hypoglycemia are already lost in established type 1 diabetes mellitus. Further, the epinephrine response is typically attenuated, i.e., the glycemic threshold for the epinephrine response is shifted to lower plasma glucose concentrations, which can be aggravated by previous incidents of hypoglycemia.

The following factors contribute to hypoglycemic unawareness:

- There may be autonomic neuropathy

- The brain may have become desensitized to hypoglycemia

- The person may be using medicines which mask the hypoglycemic symptoms

The guidelines for preventing impaired fasting glucose are the same as those given for preventing type 2 diabetes in general. If these are adhered to, the progression to clinical diabetes can be slowed or halted. In some cases, a complete reversal of IFG can be achieved. Certain risk factors, such as being of Afro-Caribbean or South Asian ethnicity, as well as increasing age, are unavoidable, and such individuals may be advised to follow these guidelines, as well as monitor their blood glucose levels, more closely.

There are several genetic forms of hyperinsulinemic hypoglycemia:

Possible causes include:

- Neoplasm

- Pancreatic cancer

- Polycystic ovary syndrome (PCOS)

- Trans fats

The signs of diabetes mellitus are caused by a persistently high blood glucose concentration, which may be caused by either insufficient insulin, or by a lack of response to insulin. Most cats have a type of diabetes mellitus similar to human diabetes mellitus type 2, with β-cell dysfunction and insulin resistance. Factors which contribute to insulin resistance include obesity and endocrine diseases such as acromegaly. Acromegaly affects 20–30% of diabetic cats; it can be diagnosed by measuring the concentration of insulin-like growth factor-1 (IGF-1) in the blood.

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.

As impaired fasting glucose is considered a precursor condition for type 2 diabetes, it shares the same environmental and genetic risk factors.

Oxyhyperglycemia is most commonly caused by early dumping syndrome, but it can rarely caused by other conditions like Graves' disease. It was first described by Lawrence et al. in 1936 as often happening after gastroenterostomy. It is seen in most forms of gastrectomy, gastric bypass and gastrostomy procedures, all of which are surgical causes of dumping syndrome.

Although this hypothesis is well known among clinicians and individuals with diabetes, there is little scientific evidence to support it. Clinical studies indicate that a high fasting glucose in the morning is more likely because the insulin given on the previous evening fails to last long enough. Studies from 2007 onwards using continuous glucose monitoring show that a high glucose in the morning is not preceded by a low glucose during the night. Furthermore, many individuals with hypoglycemic episodes during the night don't wake due to a failure of release of epinephrine during nocturnal hypoglycemia. Thus, Somogyi's theory is not assured and may be refuted.

These are associated with insulin resistance and are risk factors for the development of type 2 diabetes mellitus. Those in this stratum (IGT or IFG) are at increased risk of cardiovascular disease. Of the two, impaired glucose tolerance better predicts cardiovascular disease and mortality.

In a way, prediabetes is a misnomer since it is an early stage of diabetes. It now is known that the health complications associated with type 2 diabetes often occur before the medical diagnosis of diabetes is made.

The NIH states: "The causes of most cases of reactive hypoglycemia are still open to debate. Some researchers suggest that certain people may be more sensitive to the body’s normal release of the hormone epinephrine, which causes many of the symptoms of hypoglycemia. Others believe deficiencies in glucagon secretion might lead to reactive hypoglycemia.

Stomach surgery or hereditary fructose intolerance are believed to be causes, albeit uncommon, of reactive hypoglycemia. myo-Inositol or D-chiro-inositol withdrawal can cause temporary reactive hypoglycemia.

There are different kinds of reactive hypoglycemia:

1. Alimentary hypoglycemia (consequence of dumping syndrome; it occurs in about 15% of people who have had stomach surgery)

2. Hormonal hypoglycemia (e.g., hypothyroidism)

3. Helicobacter pylori-induced gastritis (some reports suggest this bacteria may contribute to the occurrence of reactive hypoglycemia)

4. Congenital enzyme deficiencies (hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood)

5. Late hypoglycemia (occult diabetes; characterized by a delay in early insulin release from pancreatic β-cells, resulting in initial exaggeration of hyperglycemia during a glucose tolerance test)

"Idiopathic reactive hypoglycemia" is a term no longer used because researchers now know the underlying causes of reactive hypoglycemia and have the tools to perform the diagnosis and the pathophysiological data explaining the mechanisms.

To check if there is real hypoglycemia when symptoms occur, neither an oral glucose tolerance test nor a breakfast test is effective; instead, a hyperglucidic breakfast test or ambulatory glucose testing is the current standard.

The body requires a relatively constant input of glucose, a sugar produced upon digestion of carbohydrates, for normal functioning. Glucagon and insulin are among the hormones that ensure a normal range of glucose in the human body. Upon consumption of a meal, blood sugar normally rises, which triggers pancreatic cells to produce insulin. This hormone initiates the absorption of the just-digested blood glucose as glycogen into the liver for metabolism or storage, thereby lowering glucose levels in the blood. In contrast, the hormone glucagon is released by the pancreas as a response to lower than normal blood sugar levels. Glucagon initiates uptake of the stored glycogen in the liver into the bloodstream so as to increase glucose levels in the blood.

Sporadic, high-carbohydrate snacks and meals are deemed the specific causes of sugar crashes. The “crash” one feels is due to the rapid increase and subsequent decline of blood sugar in the body system as one begins and ceases consumption of high-sugar foods. More insulin than is actually needed is produced in response to the large, rapid ingestion of sugary foods.

Significant hypoglycemia appears to increase the risk of cardiovascular disease.

If known causes for ketotic hypoglycemia such as the ketotic Glycogen Storage Disease subtypes can be ruled out, it has been proposed that this condition simply represents the extreme edge of the normal population in terms of tolerance for fasting and ability to maintain normoglycemia. It is also possible that some children given this diagnosis have still-undiscovered defects of metabolism which will eventually be identified.

Gestational diabetes affects 3–10% of pregnancies, depending on the population studied.

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.