diabetes pathophysiology

Pathophysiology

The fluctuation of blood sugar (red) and the sugar-lowering hormone insulin (blue) in humans during the course of a day with three meals — one of the effects of a sugar-rich vs a starch-rich meal is highlighted.

Mechanism of insulin release in normal pancreatic beta cells — insulin production is more or less constant within the beta cells. Its release is triggered by food, chiefly food containing absorbable glucose.

Insulin is the principal hormone that regulates the uptake of glucose from the blood into most cells of the body, especially liver, adipose tissue and muscle, except smooth muscle, in which insulin acts via the IGF-1. Therefore, deficiency of insulin or the insensitivity of its receptors plays a central role in all forms of diabetes mellitus.^[50]

The body obtains glucose from three main places: the intestinal absorption of food; the breakdown of glycogen, the storage form of glucose found in the liver; and gluconeogenesis, the generation of glucose from non-carbohydrate substrates in the body.^[51] Insulin plays a critical role in balancing glucose levels in the body. Insulin can inhibit the breakdown of glycogen or the process of gluconeogenesis, it can stimulate the transport of glucose into fat and muscle cells, and it can stimulate the storage of glucose in the form of glycogen.^[51]

Insulin is released into the blood by beta cells (β-cells), found in the islets of Langerhans in the pancreas, in response to rising levels of blood glucose, typically after eating. Insulin is used by about two-thirds of the body's cells to absorb glucose from the blood for use as fuel, for conversion to other needed molecules, or for storage. Lower glucose levels result in decreased insulin release from the beta cells and in the breakdown of glycogen to glucose. This process is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin.^[52]

If the amount of insulin available is insufficient, if cells respond poorly to the effects of insulin (insulin insensitivity or insulin resistance), or if the insulin itself is defective, then glucose will not be absorbed properly by the body cells that require it, and it will not be stored appropriately in the liver and muscles. The net effect is persistently high levels of blood glucose, poor protein synthesis, and other metabolic derangements, such as acidosis.^[51]

When the glucose concentration in the blood remains high over time, the kidneys will reach a threshold of reabsorption, and glucose will be excreted in the urine (glycosuria).^[53] This increases the osmotic pressure of the urine and inhibits reabsorption of water by the kidney, resulting in increased urine production (polyuria) and increased fluid loss. Lost blood volume will be replaced osmotically from water held in body cells and other body compartments, causing dehydration and increased thirst (polydipsia).

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diabetes management

Management

Main article: Diabetes management

Overview of management

Diabetes mellitus is a chronic disease, for which there is no known cure except in very specific situations.^[66] Management concentrates on keeping blood sugar levels as close to normal, without causing low blood sugar. This can usually be accomplished with a healthy diet, exercise, weight loss, and use of appropriate medications (insulin in the case of type 1 diabetes; oral medications, as well as possibly insulin, in type 2 diabetes).^{[citation needed]}

Learning about the disease and actively participating in the treatment is important, since complications are far less common and less severe in people who have well-managed blood sugar levels.^[67][68] The goal of treatment is an HbA_1C level of 6.5%, but should not be lower than that, and may be set higher.^[69] Attention is also paid to other health problems that may accelerate the negative effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.^[69] Specialized footwear is widely used to reduce the risk of ulceration, or re-ulceration, in at-risk diabetic feet. Evidence for the efficacy of this remains equivocal, however.
                                      

Lifestyle

See also: Diabetic diet

People with diabetes can benefit from education about the disease and treatment, good nutrition to achieve a normal body weight, and exercise, with the goal of keeping both short-term and long-term blood glucose levels within acceptable bounds. In addition, given the associated higher risks of cardiovascular disease, lifestyle modifications are recommended to control blood pressure.^[71]

Medications

See also: Anti-diabetic medication

Medications used to treat diabetes do so by lowering blood sugar levels. There are a number of different classes of anti-diabetic medications. Some are available by mouth, such as metformin, while others are only available by injection such as GLP-1 agonists. Type 1 diabetes can only be treated with insulin, typically with a combination of regular and NPH insulin, or synthetic insulin analogs.^{[citation needed]}

Metformin is generally recommended as a first line treatment for type 2 diabetes, as there is good evidence that it decreases mortality.^[72] It works by decreasing the liver's production of glucose.^[73] Several other groups of drugs, mostly given by mouth, may also decrease blood sugar in type II DM. These include agents that increase insulin release, agents that decrease absorption of sugar from the intestines, and agents that make the body more sensitive to insulin.^[73] When insulin is used in type 2 diabetes, a long-acting formulation is usually added initially, while continuing oral medications.^[72] Doses of insulin are then increased to effect.
                               

Since cardiovascular disease is a serious complication associated with diabetes, some have recommended blood pressure levels below 130/80 mmHg.^[75] However, evidence supports less than or equal to somewhere between 140/90 mmHg to 160/100 mmHg; the only additional benefit found for blood pressure targets beneath this range was an isolated decrease in stroke risk, and this was accompanied by an increased risk of other serious adverse events.^[76][77] A 2016 review found potential harm to treating lower than 140 mmHg.^[78] Among medications that lower blood pressure, angiotensin converting enzyme inhibitors (ACEIs) improve outcomes in those with DM while the similar medications angiotensin receptor blockers (ARBs) do not.^[79] Aspirin is also recommended for people with cardiovascular problems, however routine use of aspirin has not been found to improve outcomes in uncomplicated diabetes.
                           

Surgery

A pancreas transplant is occasionally considered for people with type 1 diabetes who have severe complications of their disease, including end stage kidney disease requiring kidney transplantation.^[81]

Weight loss surgery in those with obesity and type two diabetes is often an effective measure.^[82] Many are able to maintain normal blood sugar levels with little or no medications following surgery^[83] and long-term mortality is decreased.^[84] There however is some short-term mortality risk of less than 1% from the surgery.^[85]The body mass index cutoffs for when surgery is appropriate are not yet clear.^[84] It is recommended that this option be considered in those who are unable to get both their weight and blood sugar under control

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diabetes diagnosis

Diagnosis

See also: Glycated hemoglobin and Glucose tolerance test

WHO diabetes diagnostic criteria^[54][55]  edit

Condition	2 hour glucose	Fasting glucose	HbA1c
Unit	mmol/l(mg/dl)	mmol/l(mg/dl)	mmol/mol	DCCT %
Normal	<7.8 (<140)	<6.1 (<110)	<42	<6.0
Impaired fasting glycaemia	<7.8 (<140)	≥6.1(≥110) & <7.0(<126)	42-46	6.0–6.4
Impaired glucose tolerance	≥7.8 (≥140)	<7.0 (<126)	42-46	6.0–6.4
Diabetes mellitus	≥11.1 (≥200)	≥7.0 (≥126)	≥48	≥6.5

Diabetes mellitus is characterized by recurrent or persistent high blood sugar, and is diagnosed by demonstrating any one of the following:^[46]

• Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)
• Plasma glucose ≥ 11.1 mmol/l (200 mg/dl) two hours after a 75 g oral glucose load as in a glucose tolerance test
• Symptoms of high blood sugar and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)
• Glycated hemoglobin (HbA_1C) ≥ 48 mmol/mol (≥ 6.5 DCCT %).^[56]
•  

                 

A positive result, in the absence of unequivocal high blood sugar, should be confirmed by a repeat of any of the above methods on a different day. It is preferable to measure a fasting glucose level because of the ease of measurement and the considerable time commitment of formal glucose tolerance testing, which takes two hours to complete and offers no prognostic advantage over the fasting test.^[57] According to the current definition, two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.
                    

Per the World Health Organization people with fasting glucose levels from 6.1 to 6.9 mmol/l (110 to 125 mg/dl) are considered to have impaired fasting glucose.^[58]people with plasma glucose at or above 7.8 mmol/l (140 mg/dl), but not over 11.1 mmol/l (200 mg/dl), two hours after a 75 g oral glucose load are considered to have impaired glucose tolerance. Of these two prediabetic states, the latter in particular is a major risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.^[59] The American Diabetes Association since 2003 uses a slightly different range for impaired fasting glucose of 5.6 to 6.9 mmol/l (100 to 125 mg/dl).^[60]

Glycated hemoglobin is better than fasting glucose for determining risks of cardiovascular disease and death from any cause.

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