Diabetes and the Endocrine Pancreas: A Biochemical Approach

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Diabetes and the Endocrine Pancreas

Red blood cells, as well as cells of the brain, liver, kidneys, and the lining of the small intestine, do not have insulin receptors on their cell membranes and do not require insulin for glucose uptake. Although all other body cells do require insulin if they are to take glucose from the bloodstream, skeletal muscle cells and adipose cells are the primary targets of insulin. The presence of food in the intestine triggers the release of gastrointestinal tract hormones such as glucose-dependent insulinotropic peptide previously known as gastric inhibitory peptide. This is in turn the initial trigger for insulin production and secretion by the beta cells of the pancreas.

Once nutrient absorption occurs, the resulting surge in blood glucose levels further stimulates insulin secretion. Precisely how insulin facilitates glucose uptake is not entirely clear. However, insulin appears to activate a tyrosine kinase receptor, triggering the phosphorylation of many substrates within the cell. These multiple biochemical reactions converge to support the movement of intracellular vesicles containing facilitative glucose transporters to the cell membrane.

In the absence of insulin, these transport proteins are normally recycled slowly between the cell membrane and cell interior. Insulin triggers the rapid movement of a pool of glucose transporter vesicles to the cell membrane, where they fuse and expose the glucose transporters to the extracellular fluid. The transporters then move glucose by facilitated diffusion into the cell interior.

Visit this link to view an animation describing the location and function of the pancreas. What goes wrong in the function of insulin in type 2 diabetes? Insulin also reduces blood glucose levels by stimulating glycolysis, the metabolism of glucose for generation of ATP. Moreover, it stimulates the liver to convert excess glucose into glycogen for storage, and it inhibits enzymes involved in glycogenolysis and gluconeogenesis.

Finally, insulin promotes triglyceride and protein synthesis. The secretion of insulin is regulated through a negative feedback mechanism. As blood glucose levels decrease, further insulin release is inhibited. The pancreatic hormones are summarized in Table 7. An increasingly common disease, diabetes mellitus has been diagnosed in more than 18 million adults in the United States, and more than , children. It is estimated that up to 7 million more adults have the condition but have not been diagnosed. In addition, approximately 79 million people in the US are estimated to have pre-diabetes, a condition in which blood glucose levels are abnormally high, but not yet high enough to be classified as diabetes.

There are two main forms of diabetes mellitus. Type 1 diabetes is an autoimmune disease affecting the beta cells of the pancreas. Certain genes are recognized to increase susceptibility. The beta cells of people with type 1 diabetes do not produce insulin; thus, synthetic insulin must be administered by injection or infusion.

This form of diabetes accounts for less than five percent of all diabetes cases. Type 2 diabetes accounts for approximately 95 percent of all cases.

Understanding the Role of Energy Homeostasis in Diabetes

About 80 to 90 percent of people with type 2 diabetes are overweight or obese. In type 2 diabetes, cells become resistant to the effects of insulin. In response, the pancreas increases its insulin secretion, but over time, the beta cells become exhausted. In many cases, type 2 diabetes can be reversed by moderate weight loss, regular physical activity, and consumption of a healthy diet; however, if blood glucose levels cannot be controlled, the diabetic will eventually require insulin.

Two of the early manifestations of diabetes are excessive urination and excessive thirst. They demonstrate how the out-of-control levels of glucose in the blood affect kidney function. The kidneys are responsible for filtering glucose from the blood. Excessive blood glucose draws water into the urine, and as a result the person eliminates an abnormally large quantity of sweet urine. The use of body water to dilute the urine leaves the body dehydrated, and so the person is unusually and continually thirsty. The person may also experience persistent hunger because the body cells are unable to access the glucose in the bloodstream.

Over time, persistently high levels of glucose in the blood injure tissues throughout the body, especially those of the blood vessels and nerves. Inflammation and injury of the lining of arteries lead to atherosclerosis and an increased risk of heart attack and stroke.

Damage to the microscopic blood vessels of the kidney impairs kidney function and can lead to kidney failure. Damage to blood vessels that serve the eyes can lead to blindness. Blood vessel damage also reduces circulation to the limbs, whereas nerve damage leads to a loss of sensation, called neuropathy, particularly in the hands and feet. Together, these changes increase the risk of injury, infection, and tissue death necrosis , contributing to a high rate of toe, foot, and lower leg amputations in people with diabetes.

Uncontrolled diabetes can also lead to a dangerous form of metabolic acidosis called ketoacidosis. Deprived of glucose, cells increasingly rely on fat stores for fuel. However, in a glucose-deficient state, the liver is forced to use an alternative lipid metabolism pathway that results in the increased production of ketone bodies or ketones , which are acidic.

Diabetes is diagnosed when lab tests reveal that blood glucose levels are higher than normal, a condition called hyperglycemia.

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The treatment of diabetes depends on the type, the severity of the condition, and the ability of the patient to make lifestyle changes. Hypoglycemia is a fact of life for most persons with type 1 diabetes and many with type 2 diabetes. Although persons with diabetes are not spared the risk for the same hypoglycemic disorders as those without diabetes, the vast majority of their hypoglycemic episodes are the result of treatment of their diabetes.

Furthermore, the pathophysiology of hypoglycemia in diabetes is distinct, and the diagnostic and management approaches are different from those in individuals without diabetes 12 , Therefore, we address hypoglycemia in persons without diabetes and in those with diabetes separately. Glucose is an obligate metabolic fuel for the brain under physiological conditions 6 , 7. That, in turn, requires maintenance of the plasma glucose level within the physiological range because blood-to-brain glucose transport is a direct function of the arterial plasma glucose concentration.

Redundant glucose counterregulatory mechanisms normally effectively prevent or rapidly correct hypoglycemia 7. The critical physiological defenses include: 1 a decrease in insulin secretion as glucose levels decline within the physiological range; 2 an increase in glucagon secretion; or, in its absence, 3 an increase in epinephrine secretion, both occurring as glucose levels decline just below the physiological range.

Increased cortisol and GH secretion are involved in defense against prolonged hypoglycemia. If these defenses fail to abort the episode, plasma glucose levels will continue to fall.

Because external losses are normally negligible, hypoglycemia develops when the sum of glucose utilization from the circulation largely by the brain but also by obligatory glycolytic tissues, such as the renal medullae and erythrocytes, and insulin-sensitive tissues, such as muscle exceeds the sum of glucose delivery into the circulation from ingested carbohydrates and hepatic and renal glucose production 12 — Because of the capacity to increase endogenous glucose production substantially, hypoglycemia is typically the result of absolutely low rates of glucose production or rates of glucose production that are low relative to high rates of glucose utilization.

These may include computed tomography or MRI, transabdominal and endoscopic ultrasonography, and, if necessary, selective pancreatic arterial calcium injections with measurements of hepatic venous insulin levels. Because hypoglycemic disorders are rare in persons without diabetes, recommendations for their evaluation and management must rely largely on clinical experience.

However, the implicit alternative approach to the recommendations we propose is a much less thorough clinical evaluation. Compared with this alternative, the large potential benefit of a thorough workup upgrades the quality of the evidence to moderate. Of note, however, much lower quality evidence supports the recommended strategy when compared with strategies with minor modifications or omissions.

Causes of hypoglycemia are outlined in Table 1. Drugs are the most common cause of hypoglycemia 12 , 18 — In addition to insulin and insulin secretagogues, offending drugs include alcohol 12 , 19 , 20 among others, as detailed below. Hypoglycemia sometimes occurs during sepsis and in other critical illnesses including renal or hepatic failure, and rarely in cortisol deficiency Hypoglycemia caused by nonislet cell tumors or endogenous hyperinsulinism is rare 12 — It can also be accidental, surreptitious, or even malicious Hypoglycemia can occur as a result of hyperinsulinism in the absence of previous gastric surgery or after Roux-en-Y gastric bypass for obesity.

It can also be caused by an antibody to insulin 12 , 13 , The traditional classification of hypoglycemia in persons without diabetes—postabsorptive fasting vs. Persons with an insulinoma, who typically have postabsorptive hypoglycemia, may experience postprandial hypoglycemia, and post-gastric-bypass patients, who typically have postprandial hypoglycemia, may have symptoms when fasting. Indeed, some disorders, e. A more useful categorization for the clinician is to establish whether the patient is seemingly well or has the burden of a potentially relevant treatment or disease.

With respect to the latter, it cannot be overemphasized that in any patient with hypoglycemia, mediation by a medication must be considered. Many drugs in addition to insulin, insulin secretagogues, and alcohol have been reported to cause hypoglycemia 12 — 15 , 18 — 21 , Many of these are listed in Table 2 Drugs other than antihyperglycemic agents and alcohol reported to cause hypoglycemia Drugs, often in the setting of critical illnesses including renal failure, are the most common cause of hypoglycemia in hospitals Again, insulin or insulin secretagogues are common offending drugs 18 , 25 , particularly when administered when enteral or parenteral nutrition is interrupted or when sensitivity to insulin is increased e.

Hypoglycemia is a sentinel event for many of the systems errors that compromise the safety of hospitalized patients These include failure to reconcile admission orders with preadmission medications and diet, frequent transfers between hospital units, frequent travel of patients for radiological and surgical procedures and other diagnostic and therapeutic interventions, and inappropriate use of an insulin sliding scale. Persons with a hypoglycemic disorder present clinically with a history either of discrete spells compatible with hypoglycemia or of a serendipitously measured low plasma glucose concentration.

Careful elicitation of the history of the spells, noting the specific symptoms, their timing and duration, and any aggravating and relieving factors, is essential for the formulation of a diagnostic course of action. Persons with only neurogenic symptoms with no documented low glucose levels are unlikely to have a hypoglycemic disorder. However, even one episode of neuroglycopenia warrants a diagnostic evaluation. Initially, the history including exposure to any medications , the physical examination, and a careful review of available laboratory data guide the evaluation.

A Biochemical Approach

These will usually either provide clues to a cause of hypoglycemia or exclude hypoglycemia caused by acknowledged medications, critical illnesses, hormone deficiencies, or a nonislet cell tumor Table 1. A test of adrenocortical function is reasonable, although adrenocortical failure is not commonly found as a cause of hypoglycemia in adults in the absence of other clinical clues.

A seemingly low plasma cortisol concentration measured during spontaneous hypoglycemia is not sufficient evidence of adrenocortical insufficiency because of the effect of recurrent hypoglycemia to shift glycemic thresholds for cortisol secretion to lower plasma glucose concentrations Although hypoglycemia in patients with nonislet cell tumors is often the result of tumor overproduction of incompletely processed IGF-II 27 , hypoglycemia attributed to overproduction of IGF-I has also been reported Nonislet cell tumor hypoglycemia is usually, but not invariably, associated with large, clinically apparent mesenchymal tumors.

This form of IGF-II binds poorly to its binding proteins and therefore more freely penetrates tissue spaces.

The Endocrine Pancreas – Anatomy and Physiology

Endogenous insulin secretion is suppressed appropriately in nonislet cell tumor hypoglycemia. In a seemingly well individual, the differential diagnosis narrows to two general categories: accidental, surreptitious, or even malicious hypoglycemia and endogenous hyperinsulinism 12 — Careful consideration of the former possibility 22 should precede a systematic assessment of the latter possibility.

Pharmacy errors e. Surreptitious hypoglycemia 22 , 32 — 35 is more common in people with knowledge of, and access to, glucose-lowering medications. Malicious hypoglycemia 22 , 36 , 37 can be accomplished by administration of insulin or an insulin secretagogue. Clinically, insulinoma is characterized by spells of neuroglycopenia due to endogenous hyperinsulinemic hypoglycemia occurring primarily in the fasting state but occasionally only in the postprandial period 23 , 38 , The incidence is approximately 1 in , patient-years It may occur in all ethnic groups and at any age and has a slight predominance in women.

Recurrences before 4 yr have elapsed from the initial removal of the tumor suggest fracture of the insulinoma at the time of the original enucleation Long-term survival is the rule for patients who have undergone successful insulinoma removal The noninsulinoma pancreatogenous hypoglycemia syndrome NIPHS is characterized by spells of neuroglycopenia due to endogenous hyperinsulinemic hypoglycemia typically, but not invariably, after a meal 42 — There is a predominance in men.

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Radiological localization procedures are invariably negative. Confirmation of islet hyperfunction depends on a positive selective arterial calcium stimulation test.