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.

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.

Diabetic coma is a reversible form of coma found in people with diabetes mellitus. It is a medical emergency.

Three different types of diabetic coma are identified:

1. Severe low blood sugar in a diabetic person

2. Diabetic ketoacidosis (usually type 1) advanced enough to result in unconsciousness from a combination of a severely increased blood sugar level, dehydration and shock, and exhaustion

3. Hyperosmolar nonketotic coma (usually type 2) in which an extremely high blood sugar level and dehydration alone are sufficient to cause unconsciousness.

In most medical contexts, the term diabetic coma refers to the diagnostical dilemma posed when a physician is confronted with an unconscious patient about whom nothing is known except that they have diabetes. An example might be a physician working in an emergency department who receives an unconscious patient wearing a medical identification tag saying DIABETIC. Paramedics may be called to rescue an unconscious person by friends who identify them as diabetic. Brief descriptions of the three major conditions are followed by a discussion of the diagnostic process used to distinguish among them, as well as a few other conditions which must be considered.

An estimated 2 to 15 percent of diabetics will suffer from at least one episode of diabetic coma in their lifetimes as a result of severe hypoglycemia.

People with type 1 diabetes mellitus who must take insulin in full replacement doses are most vulnerable to episodes of hypoglycemia. It is usually mild enough to reverse by eating or drinking carbohydrates, but blood glucose occasionally can fall fast enough and low enough to produce unconsciousness before hypoglycemia can be recognized and reversed. Hypoglycemia can be severe enough to cause unconsciousness during sleep. Predisposing factors can include eating less than usual or prolonged exercise earlier in the day. Some people with diabetes can lose their ability to recognize the symptoms of early hypoglycemia.

Unconsciousness due to hypoglycemia can occur within 20 minutes to an hour after early symptoms and is not usually preceded by other illness or symptoms. Twitching or convulsions may occur. A person unconscious from hypoglycemia is usually pale, has a rapid heart beat, and is soaked in sweat: all signs of the adrenaline response to hypoglycemia. The individual is not usually dehydrated and breathing is normal or shallow. Their blood sugar level, measured by a glucose meter or laboratory measurement at the time of discovery, is usually low but not always severely, and in some cases may have already risen from the nadir that triggered the unconsciousness.

Unconsciousness due to hypoglycemia is treated by raising the blood glucose with intravenous glucose or injected glucagon.

DKA most frequently occurs in those who already have diabetes, but it may also be the first presentation in someone who had not previously been known to be diabetic. There is often a particular underlying problem that has led to the DKA episode; this may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young people with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain.

Diabetic ketoacidosis may occur in those previously known to have diabetes mellitus type 2 or in those who on further investigations turn out to have features of type 2 diabetes (e.g. obesity, strong family history); this is more common in African, African-American and Hispanic people. Their condition is then labeled "ketosis-prone type 2 diabetes".

Drugs in the gliflozin class (SGLT2 inhibitors), which are generally used for type 2 diabetes, have been associated with cases of diabetic ketoacidosis where the blood sugars are not significantly elevated ("euglycemic DKA"). This may be because they were being used in people with type 1 diabetes, but in those with type 2 diabetes it may be as a result of an increase in glucagon levels.

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.

Attacks of DKA can be prevented in those known to have diabetes to an extent by adherence to "sick day rules"; these are clear-cut instructions to person on how to treat themselves when unwell. Instructions include advice on how much extra insulin to take when sugar levels appear uncontrolled, an easily digestible diet rich in salt and carbohydrates, means to suppress fever and treat infection, and recommendations when to call for medical help.

People with diabetes can monitor their own ketone levels when unwell and seek help if they are elevated.

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.

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

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.

Significant hypoglycemia appears to increase the risk of cardiovascular disease.

The most common cause of hypoglycemia is medications used to treat diabetes mellitus such as insulin, sulfonylureas, and biguanides. Risk is greater in diabetics who have eaten less than usual, exercised more than usual, or drunk alcohol. Other causes of hypoglycemia include kidney failure, certain tumors, liver disease, hypothyroidism, starvation, inborn errors of metabolism, severe infections, reactive hypoglycemia, and a number of drugs including alcohol. Low blood sugar may occur in babies who are otherwise healthy who have not eaten for a few hours. Inborn errors of metabolism may include the lack of an enzyme to make glycogen (glycogen storage type 0).

Nonketotic hyperosmolar syndrome (also known as hyperglycemic hyperosmolar syndrome) is a rare but extremely serious complication of untreated canine diabetes, which is a medical emergency. It shares the symptoms of extreme hyperglycemia, dehydration, and lethargy with ketoacidosis; because there is some insulin in the system, the body does not begin to turn to using fat as its energy source and there is no ketone production. There is not sufficient insulin available to the body for proper uptake of glucose, but there is enough to prevent ketone formation. The problem of dehydration in NHS is more profound than in diabetic ketoacidosis. Seizures and coma are possible. Treatment is similar to that of ketoacidosis, with the exceptions being that NHS requires that the blood glucose levels and rehydration be normalized at a slower rate than for DKA; cerebral edema is possible if the treatment progresses too rapidly.

Hypoglycemia, or low blood glucose, can happen even with care, since insulin requirements can change without warning. Some common reasons for hypoglycemia include increased or unplanned exercise, illness, or medication interactions, where another medication the effects of the insulin. Vomiting and diarrhea episodes can bring on a hypoglycemia reaction, due to dehydration or simply a case of too much insulin and not enough properly digested food. Symptoms of hypoglycemia need to be taken seriously and addressed promptly. Since serious hypoglycemia can be fatal, it is better to treat a suspected incident than to fail to respond quickly to the signs of actual hypoglycemia. Dr. Audrey Cook addressed the issue in her 2007 article on diabetes mellitus: "Hypoglycemia is deadly; hyperglycemia is not. Owners must clearly understand that too much insulin can kill, and that they should call a veterinarian or halve the dose if they have any concerns about a pet's well-being or appetite. Tell owners to offer food immediately if the pet is weak or is behaving strangely."

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.

Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.

Diabetes mellitus is rare in cats younger than five years old. Burmese cats in Europe and Australia have increased risk of developing diabetes mellitus; American Burmese cats do not have this increased risk due to genetic diffences between American Burmese and Burmese in other parts of the world.

In non-diabetic persons, ketonuria may occur during acute illness or severe stress. Approximately 15% of hospitalized patients may have ketonuria, even though they do not have diabetes. In a diabetic patient, ketone bodies in the urine suggest that the patient is not adequately controlled and that adjustments of medication, diet, or both should be made promptly. In the non diabetic patient, ketonuria reflects a reduced carbohydrate metabolism and an increased fat metabolism.

As insulin is required for glucose uptake, hyperglycemia in diabetes mellitus does not result in a net increase in intracellular glucose in most cells. However, chronic dysregulated blood glucose in diabetes is toxic to cells of the vascular endothelium which passively assimilate glucose. That is, cells in which insulin is not required for intercellular transport of glucose, most-notably the pericytes of the microvasculature. In addition to direct glucose-induced damage by (e.g.) glycation, pericytes express enzymes which convert glucose into osmologically-active metabolites such as sorbitol leading to hypertonic cell lysis.

Over time, pericyte death may result in reduced capillary integrity; subsequently, there is leaking of albumin and other proteins into fluid compartments. The glomeruli of the kidneys are especially sensitive – see diabetic nephropathy – where protein leakage caused by late-stage angiopathy results in diagnostic proteinuria and eventually renal failure. In diabetic retinopathy the end-result is often blindness due to irreversible retinal damage.

Hyperosmolar syndrome may take a long duration - days and weeks - to develop. However, certain signs and symptoms may indicate that such a condition is developing. Some of the signs include the following:

1. Excessive thirst despite frequently taking water / other liquids

2. Continued high level of blood sugar

3. Dry and/ or parched mouth

4. Frequency of urination increases

5. Pulse rate becomes rapid

6. Shortness of breath with exertion

7. Skin becomes dry and warm and there is no sweating

8. Sleepiness and/ or a condition of confusion

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 mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.

As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot). Small infections can progress to ulceration and this may require amputation.

There are several genetic forms of hyperinsulinemic hypoglycemia:

Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease as well as neuropathy may have an autoimmune basis, as well. Women with type 1 DM have a 40% higher risk of death as compared to men with type 1 DM. The life expectancy of an individual with type 1 diabetes is 11 years less for men and 13 years less for women.