Insulin resistance

One of insulin's various jobs is to regulate delivery of glucose into cells to provide them with energy.[1] Insulin resistant cells are not able to take in glucose, amino acids and fatty acids. Thus, glucose, fatty acids and amino acids 'leak' out of the cells. A decrease in insulin/glucagon ratio inhibits glycolysis which in turn decreases energy production. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions.[2] Certain cell types such as fat and muscle cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. This normal reduction in the liver’s glucose production may not occur in people with insulin resistance.[3]

Dietary fat has long been implicated as a driver of insulin resistance. Studies on animals observed significant insulin resistance in rats after just 3 weeks on a high-fat diet.[9] Large quantities of saturated, monounsaturated, and polyunsaturated (omega-6) fats all appear to be harmful to rats to some degree, compared to large amounts of starch, but saturated fat appears to be the most effective at producing IR.[10] This is partly caused by direct effects of a high-fat diet on blood markers, but, more significantly, ad libitum high-fat diet has the tendency to result in caloric intake that's far in excess of animals' energy needs, resulting in rapid weight gain. In humans, statistical evidence is more equivocal. Being insensitive to insulin is still positively correlated with fat intake, and negatively correlated with dietary fiber intake [11], but both these factors are also correlated with excess body weight.

The effect of dietary fat is largely or completely overridden if the high-fat diet is modified to contain nontrivial quantities (in excess of 5–10% of total fat intake) of polyunsaturated omega-3 fatty acids.[10][12][13] This protective effect is most established with regard to the so-called "marine long-chain omega-3 fatty acids", EPA and DHA, found in fish oil;

Once established, insulin resistance would result in increased circulating levels of insulin. Since insulin is the primary hormonal signal for energy storage into fat cells, which tend to retain their sensitivity in the face of hepatic and skeletal muscle resistance, IR stimulates the formation of new fatty tissue and accelerates weight gain.[38]

Studies show that high levels of cortisol within the bloodstream from the digestion of animal protein can contribute to the development of insulin resistance.[41][42] Additionally, animal protein, because of its high content of purine, causes blood pH to become acidic. Several studies conclude that high uric acid level apart from other contributing factors by itself may be a significant cause of insulin resistance[43].

Vitamin D deficiency is also associated with insulin resistance[44].

Signs and symptoms

These depend on poorly understood variations in individual biology and consequently may not be found with all people diagnosed with insulin resistance.

Brain fogginess and inability to focus.
High blood sugar.
Intestinal bloating – most intestinal gas is produced from carbohydrates in the diet, mostly those that humans cannot digest and absorb.
Sleepiness, especially after meals.
Weight gain, fat storage, difficulty losing weight – for most people, excess weight is from high fat storage; the fat in IR is generally stored in and around abdominal organs in both males and females. It is currently suspected that hormones produced in that fat are a precipitating cause of insulin resistance.
Increased blood triglyceride levels.
Increased blood pressure. Many people with hypertension are either diabetic or pre-diabetic and have elevated insulin levels due to insulin resistance. One of insulin's effects is to control arterial wall tension throughout the body.
Increased pro-inflammatory cytokines associated with cardiovascular disease.
Depression. Due to the deranged metabolism resulting from insulin resistance, psychological effects, including depression, are not uncommon.
Acanthosis nigricans.
Increased hunger.

Particular physiological conditions and environmental factors:

> 40–45 years of age;[5][6]
obesity;[5][6]
your body storing fat predominantly in the abdomen, as opposed to storing it in hips and thighs.[6]
sedentary lifestyle, lack of physical exercise[5][6]
hypertension;[5]
high triglyceride level (Hypertriglyceridemia);[5]
low level of "good cholesterol";[5]
pre-diabetes, your sugar levels in blood have been too high in the past, i.e. your body has previously shown slight problems with its production and usage of insulin ("previous evidence of impaired glucose homeostasis";[5][6]
having developed gestational diabetes during past pregnancies;[5][6]
giving birth to a baby weighing more than 9 pounds (a bit over 4 kilograms)[5][6]

Pathology:
Obesity and Overweight (BMI > 25);
Metabolic syndrome (Hyperlipidemia + HDL cholesterol level < 0.90 mmol/L or triglyceride level >2.82 mmol/L); Hypertension (>140/90 mmHg) or arteriosclerosis;
Liver pathologies;
Infection (Hepatitis C[7]);
Haemochromatosis;
Gastroparesis;
Polycystic ovary syndrome (PCOS);
Hypercortisolism (e.g., steroid use or Cushing's disease);[8]
Medication (e.g., glucosamine, rifampicin, isoniazid, olanzapine, risperidone, progestogens, corticosteroids, glucocorticoids, methadone, many antiretrovirals).



Diabetes_mellitus

Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond to the insulin that is produced.[2] This high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

There are three main types of diabetes mellitus (DM).

Type 1 DM results from the body's failure to produce insulin, and currently requires the person to inject insulin or wear an insulin pump. This form was previously referred to as "insulin-dependent diabetes mellitus" (IDDM) or "juvenile diabetes".

Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly, sometimes combined with an absolute insulin deficiency. This form was previously referred to as non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes".

The third main form, gestational diabetes occurs when pregnant women without a previous diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2 DM.

The classic symptoms of untreated diabetes are loss of weight, polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).[11] Symptoms may develop rapidly (weeks or months) in type 1 diabetes, while they usually develop much more slowly and may be subtle or absent in type 2 diabetes.

Prolonged high blood glucose can cause glucose absorption in the lens of the eye, which leads to changes in its shape, resulting in vision changes. Blurred vision is a common complaint leading to a diabetes diagnosis. A number of skin rashes that can occur in diabetes are collectively known as diabetic dermadromes.

People (usually with type 1 diabetes) may also present with diabetic ketoacidosis, a state of metabolic dysregulation characterized by the smell of acetone, a rapid, deep breathing known as Kussmaul breathing, nausea, vomiting and abdominal pain, and altered states of consciousness.


Lactose intolerance

Lactose intolerance, also called lactase deficiency and hypolactasia, is the inability to digest lactose, a sugar found in milk and to a lesser extent milk-derived dairy products. It is not a disorder as such, but a genetically-determined characteristic.

Lactose intolerant individuals have insufficient levels of lactase, an enzyme that catalyzes hydrolysis of lactose into glucose and galactose, in their digestive system. In most cases this causes symptoms which may include abdominal bloating and cramps, flatulence, diarrhea, nausea, borborygmi (rumbling stomach), or vomiting[1] after consuming significant amounts of lactose. Some studies have produced evidence that milk consumption by lactose intolerant individuals may be a significant cause of inflammatory bowel disease.[2][3][4]

Most mammals normally cease to produce lactase, becoming lactose intolerant, after weaning, but some human populations have developed lactase persistence, in which lactase production continues into adulthood.

The principal symptom of lactose intolerance is an adverse reaction to products containing lactose (primarily milk), including abdominal bloating and cramps, flatulence, diarrhea, nausea, borborygmi (rumbling stomach) and vomiting (particularly in adolescents). These appear thirty minutes to two hours after consumption.[1] The severity of symptoms typically increases with the amount of lactose consumed; most lactose-intolerant people can tolerate a certain level of lactose in their diet without ill-effect.[16][17]

Bacteria in the colon are able to metabolise lactose, and the resulting fermentation produces copious amounts of gas (a mixture of hydrogen, carbon dioxide and methane) that causes the various abdominal symptoms. The unabsorbed sugars and fermentation products also raise the osmotic pressure of the colon, resulting in an increased flow of water into the bowels (diarrhea).[19]


Fructose intolerance

Hereditary fructose intolerance (HFI) is an inborn error of fructose metabolism caused by a deficiency of the enzyme aldolase B. Individuals affected with HFI are asymptomatic until they ingest fructose, sucrose, or sorbitol. If fructose is ingested, the enzymatic block at aldolase B causes an accumulation of fructose-1-phosphate. This accumulation has downstream effects on gluconeogenesis and regeneration of adenosine triphosphate (ATP). Symptoms of HFI include vomiting, hypoglycemia, jaundice, hemorrhage, hepatomegaly, hyperuricemia and potentially kidney failure. While HFI is not clinically a devastating condition, there are reported deaths in infants and children as a result of the metabolic consequences of HFI. Death in HFI is always associated with problems in diagnosis.[1]

The key identifying feature of HFI is the appearance of symptoms with the introduction of fructose to the diet.[2][3] Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. In the past, infants often became symptomatic when they were introduced to formulas that were sweetened with fructose or sucrose. These sweeteners are not common in formulas used today.[2] Symptoms such as vomiting, nausea, restlessness, pallor, sweating, trembling and lethargy can also first present in infants when they are introduced to fruits and vegetables. These can progress to apathy, coma and convulsions if the source is not recognized early.[2]

When patients are diagnosed with HFI, a dietary history will often reveal an aversion to fruit and other foods that contain large amounts of fructose. Most adult patients do not have any dental caries.[2][3]


Galactosemia

Galactosemia (British Galactosaemia) is a rare genetic metabolic disorder that affects an individual's ability to metabolize the sugar galactose properly. Although the sugar, lactose, metabolizes to galactose, galactosemia is not related to and should not be confused with lactose intolerance. Galactosemia follows an autosomal recessive mode of inheritance that confers a deficiency in an enzyme responsible for adequate galactose degradation.

Lactose in food (such as dairy products) is broken down by the enzyme lactase into glucose and galactose. In individuals with galactosemia, the enzymes needed for further metabolism of galactose are severely diminished or missing entirely, leading to toxic levels of galactose 1-phosphate in various tissues as in the case of classic galactosemia, resulting in hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage, and ovarian failure. Without treatment, mortality in infants with galactosemia is about 75%.


Glycogen storage disease

Glycogen storage disease (GSD, also glycogenosis and dextrinosis) is the result of defects in the processing of glycogen synthesis or breakdown within muscles, liver, and other cell types.[1] GSD has two classes of cause: genetic and acquired. Genetic GSD is caused by any inborn error of metabolism (genetically defective enzymes) involved in these processes. In livestock, acquired GSD is caused by intoxication with the alkaloid castanospermine.[2]

Overall, according to a study in British Columbia, approximately 2.3 children per 100 000 births (1 in 43,000) have some form of glycogen storage disease.[3] In the United States, they are estimated to occur in 1 per 20,000-25,000 births.[4] A Dutch study estimated it to be 1 in 40,000.[5]
Types
Micrograph of glycogen storage disease with histologic features consistent with Cori disease. Liver biopsy. H&E stain.

There are eleven (11) distinct diseases that are commonly considered to be glycogen storage diseases (some previously thought to be distinct have been reclassified). (Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is often classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.)

GSD type VIII: In the past, considered a distinct condition.[6] Now classified with VI.[7] Has been described as X-linked recessive.[8]

GSD type X: In the past, considered a distinct condition.[9][10] Now classified with VI.[7]


Glucose tolerance test

A glucose tolerance test is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood.[1] The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia and acromegaly, or rarer disorders of carbohydrate metabolism. In the most commonly performed version of the test, an oral glucose tolerance test (OGTT), a standard dose of glucose is ingested by mouth and blood levels are checked two hours later. Many variations of the GTT have been devised over the years for various purposes, with different standard doses of glucose, different routes of administration, different intervals and durations of sampling, and various substances measured in addition to blood glucose.

Preparation

The patient is instructed not to restrict carbohydrate intake in the days or weeks before the test. The test should not be done during an illness, as results may not reflect the patient's glucose metabolism when healthy. A full adult dose should not be given to a person weighing less than 43 kg (94 lb), or exaggerated glucoses may produce a false positive result. Usually the OGTT is performed in the morning as glucose tolerance can exhibit a diurnal rhythm with a significant decrease in the afternoon. The patient is instructed to fast (water is allowed) for 8–12 hours prior to the tests.

Procedure

A zero time (baseline) blood sample is drawn.
The patient is then given a measured dose (below) of glucose solution to drink within a 5 minute time frame.
Blood is drawn at intervals for measurement of glucose (blood sugar), and sometimes insulin levels. The intervals and number of samples vary according to the purpose of the test. For simple diabetes screening, the most important sample is the 2 hour sample and the 0 and 2 hour samples may be the only ones collected. A laboratory may continue to collect blood for up to 6 hours depending on the protocol requested by the physician.

Dose of glucose and variations

In the US, dosing is by weight, and since the late 1970s has been 1.75 grams of glucose per kilogram of body weight, to a maximum dose of 75g. Prior to 1975 a dose of 100g was often used.
The WHO recommendation is for a 75g oral dose in all adults: the dose is adjusted for weight only in children.[2] The dose should be drunk within 5 minutes.
A variant is often used in pregnancy to screen for gestational diabetes, with a screening test of 50 grams over one hour. If elevated, this is followed with a test of 100 grams over three hours.
In UK General Practice, the standard glucose load is provided by 394ml of the sports drink Lucozade (original flavour only), which the patient is asked to supply.[3][4]

Substances measured and variations

If renal glycosuria (sugar excreted in the urine despite normal levels in the blood) is suspected, urine samples may also be collected for testing along with the fasting and 2 hour blood tests.
Interpretation of OGTT results

Fasting plasma glucose (measured before the OGTT begins) should be below 6.1 mmol/L (110 mg/dL). Fasting levels between 6.1 and 7.0 mmol/L (110 and 125 mg/dL) are borderline ("impaired fasting glycaemia", and fasting levels repeatedly at or above 7.0 mmol/L (126 mg/dL) are diagnostic of diabetes.

A 2 hour OGTT glucose level below 7.8 mmol/L (140 mg/dL) is normal, whereas higher glucose levels indicate hyperglycemia. Blood plasma glucose between 7.8 mmol/L (140 mg/dL) and 11.1 mmol/L (200 mg/dL) indicate "impaired glucose tolerance", and levels above 11.1 mmol/L (200 mg/dL) at 2 hours confirms a diagnosis of diabetes.