Hormonal Regulation of Glucose Levels
The hallmark of diabetes is elevated blood glucose levels. This abnormal elevation is due to the decrease or absence of hormones that lower blood glucose and a cellular resistance to insulin. A review of normal fuel metabolism and the hormones responsible for glucose regulation follows.
Plasma glucose levels reflect the rate at which glucose is absorbed from the intestines and then removed from circulation to be stored as fuel. The first phase of fuel metabolism is called the fed state and encompasses the first 4 hours after ingestion of food. During this phase, the pancreas responds to increasing levels of circulating glucose by activating stored insulin called “proinsulin.” Proinsulin is a protein composed of two chains “A” and “B” of amino acids, which are held together by a bridge called a connecting peptide (c-peptide). On pancreatic detection of elevating glucose, the connecting peptide of proinsulin cleaves off. The resulting activated insulin and c-peptide enter the bloodstream. This initial burst of insulin is referred to as first phase insulin response. First phase insulin is responsible for maintaining postmeal glucose within normal limits. Insulin then passes through the portal vein into the bloodstream. Once insulin enters the bloodstream, it has a half-life of a few minutes. However, since c-peptide has a longer half-life, it is can be measured by a blood test to determine how much endogenous insulin a person releases.
During these first 4 hours of the fed state, insulin promotes the storage of glucose as glycogen in the insulin-sensitive peripheral tissues, including hepatic and muscle cells. Insulin also promotes storage of amino acids as protein and excess glucose is stored as fat. The end result is a lowering of circulating blood glucose, lipids, and other energy substrates. Besides promoting the disposal of nutrients into cells, insulin has the critical role of suppressing glucagon. Glucagon, a hormone released by the α-cells of the pancreas, stimulates the release of stored glucose (glycogen) from the liver.
During this fed state, the β-cells of the pancreas also release the recently discovered hormone amylin, a 37-amino acid polypeptide.13
Amylin compliments the action of insulin by preventing postmeal blood glucose excursions in several ways. Unlike insulin, it slows down gastric emptying, promotes a sense of satiety, and decreases the release of glucagon. People with type 1 diabetes make no amylin and those with type 2 make less than normal amounts.
Another group of newly discovered intestinal hormones, the incretins, are also released in response to nutrient ingestion. The incretins include glucose-dependent insulin-releasing peptide (GIP) and glucagon-like peptide-1 (GLP-1). GIP is secreted by the K cells of the upper intestine and GLP-1 is released from the L cells of the intestine.13
Both are secreted in response to postmeal glucose elevations and stimulate β-cell insulin secretion. In addition to increasing glucose-dependent insulin secretion, incretin hormones inhibit glucagon secretion, slow gastric emptying, and increase feelings of satiety. Incretins help to keep postmeal blood glucose levels within normal ranges. Both GIP and GLP-1 are rapidly degraded by the enzyme dipeptidyl-peptidase-inhibitor-IV. (New therapies that imitate the incretins and inhibit their breakdown will be discussed in the section “Medication for Type 2 Diabetes
.”) People with type 1 diabetes make normal amounts of the incretins, while those with type 2 secrete less of this powerful glucose-lowering hormone.13
Four to 16 hours after eating, the body enters the phase II or the postabsorptive state. This phase most often occurs during sleep and marks the end of anabolism or energy storage and begins the phase of catabolism or energy production. During this phase, since the body is not exposed to food, it must revert to stored energy for fuel. Glucagon levels rise and insulin levels decrease to a steady state, often termed basal insulin release. The main function of insulin during this phase is not to promote energy storage, but to prevent hyperglycemia. The high levels of circulating glucagon increase the breakdown of glycogen stores in the liver (glycogenolysis) to ensure an adequate supply of glucose to the brain and other glucose-dependent tissues. In addition, fat cells (adipocytes) break down triglycerides and release free fatty acids (FFAs) to be used as energy by the liver and skeletal muscles. The brain will only use glucose for fuel due to its inability to use FFAs as fuel. Many individuals with type 2 diabetes experience morning fasting hyperglycemia due to the dominance of glycogen and the relative lack of insulin during this phase.13
In addition to glucagon, there are other catabolic hormones that increase the breakdown of stored fuel supplies and increase circulating glucose. They increase insulin resistance and glycogen breakdown, causing a net increase in blood glucose levels. The hormones released from the kidney, corticosteroids and epinephrine, are activated during flight-or-fight response or hypoglycemia. Other hormones including growth hormone and cortisol increase insulin resistance in early morning, causing many people with type 1 diabetes to experience the “dawn” phenomena, or an elevation in morning glucose.14
Glucose homeostasis is reliant on a complex interrelationship of hormones that activate anabolic and catabolic processes. When this precise balance is disrupted through the loss or dysfunction of insulin and other hormones, the end result is hyperglycemia.
Type 1 Diabetes Mellitus
Previously labeled “juvenile diabetes” or “insulin-dependent diabetes,” type 1 diabetes affects approximately 10% of all people with diabetes.6
The unique feature of type 1 is its’ progressive autoimmunity resulting in complete destruction of the pancreatic β-cells. Although it can occur at any age, most new cases are expressed during childhood and puberty, when insulin-resistant pubertal hormones are at their peak. To express type 1 diabetes, a genetic propensity and an environmental trigger are necessary.13
Research has not identified any one causative agent that triggers the autoimmune attack against the pancreas, but several agents are suspected.15
Viral triggers such as enteroviruses, coxsackie virus B, congenital rubella, cytomegalovirus, and mumps are suspected culprits. However, these agents are only theorized to initiate the autoimmunity of type 1 diabetes, and research on causation is ongoing. From a prevention perspective, it appears that children who are breastfed are less likely to develop type 1 diabetes.13
When 90% of the pancreas is destroyed, there is no longer enough insulin available to maintain euglycemia and the symptoms of hyperglycemia are expressed. The rate of destruction of the β-cell mass with type 1 diabetes is rapid in youth and more gradual in the older age group.13
Although the destruction of the β-cells is progressive, the onset of type 1 diabetes is usually abrupt. With only 10% of the pancreas working, there is no longer adequate insulin to maintain euglycemia. Without sufficient insulin to utilize glucose for energy, the body starts breaking down fat stores for fuel. The pace of this fat breakdown and resulting ketone bodies overwhelms the liver and, in a short time, it can no longer clear ketones at a fast enough pace. High levels of circulating ketones result in ketosis and acidosis—also called diabetes ketoacidosis. At this point, the body cells are starved for glucose and the person usually feels ill enough to seek medical help. Depending on the duration and severity of ketosis, the person with a new case of type 1 diabetes appears malnourished due to inability to store fuel, dehydrated due to osmotic diuresis, and may have abdominal pain and nausea from the ketone bodies. In an effort to blow off excess acids, the person may have rapid respirations and a their breath may smell fruity. Treatment includes fluids, insulin, electrolyte replacement, and patient and family education. Clinical presentation is usually enough to make a diagnosis of type 1 diabetes. If unsure, a diagnosis can be confirmed by antibody blood tests. Some tests used to confirm autoimmune β-cell destruction include antibodies to glutamic acid decarboxylase, islet cell autoantibodies, and insulin autoantibodies.15
Patients with type 1 diabetes will require insulin replacement for the rest of their lives. There is ongoing investigation to evaluate if type 1 diabetes can be prevented or delayed in individuals at high risk of developing type 1 diabetes. To date however, large, randomized clinical trials have failed to demonstrate treatment effect.16
These studies have improved the understanding of the immunopathogenesis and will hopefully lead to future strategies and treatments to prevent type 1 diabetes.
Type 2 Diabetes Mellitus
Unlike type 1 diabetes, type 2 diabetes (formerly referred to as adult onset or non-insulin-dependent diabetes) is not an autoimmune condition. Of all people with diabetes, 90% to 95% have type 2. Most people with type 2 diabetes are overweight and develop hyperglycemia as a result of insulin resistance and insulin deficiency. Besides being overweight, some of the risk factors for developing type 2 diabetes include physical inactivity, first-degree relative with diabetes, women who delivered a baby bigger than 9 lb (4.2 kg), or who had gestational diabetes. Other risk factors include hypertension, impaired glucose tolerance, elevated triglycerides, and other conditions associated with insulin resistance.11
In addition to these risk factors, the social milieu into which a person is born can also increase or decrease the likelihood of the expression of type 2 diabetes. Social research reveals that people of
lower socioeconomic status are more likely to express diabetes.18
This may be due to a variety of factors including lack of access to safe places to exercise, limited knowledge of healthy eating, and increased prevalence of obesity. Being overweight and obese, especially central abdominal obesity, across all populations increases in the risk of diabetes. New research has discovered that abdominal adipose tissue acts as an endocrine organ, secreting chemical mediators that increase insulin resistance and inflammation.19
β-Cell Defects Associated With Type 2 Diabetes
Type 2 diabetes is a heterogeneous group of disorders that in combination result in hyperglycemia. These disorders include β-cell death, insulin resistance, excessive hepatic glucose release, and other hormonal deficiencies.15
The cause of β-cell mass death is not known. Studies suggest that about 40% of β-cell mass is lost in individuals with impaired glucose tolerance and 60% on clinical diagnosis of diabetes.20
β-Cell loss starts 9 to 12 years before the diabetes is diagnosed.15
The rate of β-cell death is much higher in people with diabetes, although the rate of new islet cell formation is unaffected.13
Because of large clinical trials, such as the United Kingdom Prospective Diabetes Study, the natural history of type 2 diabetes is better understood. This study demonstrated that β-cell death in type 2 diabetes is progressive and continues over time.21
Upon diagnosis of type 2 diabetes, regardless if the patient is lean or overweight, beta cell mass is decreased by half. This in part explains why 30% of people with type 2 diabetes eventually require insulin therapy.22
In addition to β-cell death, there is diminished pancreatic sensitivity and insulin secretory response. This reduced response is caused by pancreatic overexposure to chronically abnormal high levels of blood glucose (sometimes termed glucose toxicity).13
As insulin secretion decreases, blood glucose levels rise above normal and thus marks the beginnings of type 2 diabetes. However, more than β-cell death and insulin deficiency is to blame.
Insulin Resistance and Cardiometabolic Syndrome
Insulin resistance refers to the inadequate response of the muscle, liver, and fat cells to insulin. As a result, glucose stays in circulation instead of being converted into energy through cellular metabolism.5
People who are overweight and obese are more likely to be insulin resistant. Contrary to popular belief, insulin resistance is not due to deficient or malfunctioning insulin cell receptors. Studies show that people with diabetes have normal amount and function of insulin receptors.13
The exact mechanism of insulin resistance is not understood but may be due to defective postinsulin receptor signal transduction mechanisms.19
Early in the process of diabetes, the pancreas oversecretes insulin in an effort to overcome insulin resistance and maintain euglycemia. Many people with insulin resistance have high levels of blood glucose and high levels of insulin circulating in their blood at the same time. As insulin resistance continues and β-cell loss worsens, blood glucose levels exceed normal levels. Morning glucose levels are elevated since there is not enough insulin to prevent nocturnal overproduction of glucose by the liver. Postmeal blood glucose levels are elevated due to several mechanisms. First, due to the defects of diabetes, the uptake of glucose by the muscle after meals is decreased by over 50%. Second, unchecked glucagon stimulates the liver to release glucose, even in a fed state. Finally, muscle and adipocytes (fat cells) are resistant to insulin, which results in high levels of FFAs. Elevated FFA worsens insulin resistance in the liver and muscle cells, increases the formation of glucose and impairs β-cell secretion. Dysfunctional adipocytes also produce chemical mediators that contribute to atherosclerosis and insulin resistance.13
This unrestrained hyperglycemia further reduces insulin sensitivity and pancreatic insulin secretion.15
In addition to decreasing β-cell function and insulin resistance, other hormone dysfunction contributes to hyperglycemia. With type 2 diabetes, the β-cells are also under producing the glucose-lowering hormone, amylin. This hormone discovered in the 1980s is secreted in a 1:1 ratio with insulin and increases satiety and lowers postmeal glucagon release. People with type 2 diabetes make less than half the normal amount of amylin. The gut hormones GLP-1 and GIP that promote satiety and decrease postmeal glucagon release are also under produced. The enzyme that breaks down these hormones called dipeptidyl-peptidase-inhibitor-IV is overactive and decreases the bioavailability of these critical hormones adding to postmeal hyperglycemia.23
Metabolic Syndrome Overview.
The term metabolic syndrome (sometimes termed insulin-resistant syndrome or cardiometabolic syndrome) refers to a clustering of risk factors that include abdominal obesity, dyslipidemia, hyperglycemia, and hypertension.24
This syndrome is a major public health challenge worldwide since it is associated with a five-fold elevated risk of type 2 diabetes and a two- to three-fold risk of CVD.25
In 1998, Reaven described a syndrome based on insulin resistance, high circulating insulin levels, hyperglycemia, elevated very-low-density lipoprotein (VLDL), decreased high-density lipoprotein (HDL) cholesterol and high blood pressure.26
Since then, there has been ongoing interest, research, and debate on definition and utility of the metabolic syndrome. The ADA and EASD have called into question the imprecision of the definition, the lack of certainty of the pathogenesis and its value in predicting CVD. These diabetes organizations stress the importance of evaluating and treating each cardiovascular risk factor; whether the person meets the diagnostic criteria for the metabolic syndrome or not.27
Ongoing research is needed to determine the predictive benefit of diagnosing someone with metabolic syndrome. In addition, there is no one universal definition for the metabolic syndrome. The most commonly referred to definitions are the World Health Organization (WHO) definition developed in 1999,28
the National Cholesterol Education Program Adult Treatment Expert Panel III (NCEP III) in 200129
and most recently the International Diabetes Federation (IDF)30
consensus panel in 2005 which has developed a worldwide consensus of the definition of the metabolic syndrome. In 2003, the American College of Endocrinology (ACE) published a position statement in collaboration with American Association of Clinical Endocrinologists (AACE) on “insulin resistance syndrome”31
(their preferred term) which avoids using a set of criteria to define metabolic syndrome, but instead focuses on the cluster of abnormalities that are more likely to occur in individuals who are insulin resistant/hyperinsulinemic and stress that diagnosis should be based on clinical judgment informed by the evaluation of risk factors. In their position paper, they specifically strive to distinguish insulin-resistant syndrome from type 2 diabetes and CVD, since their stated clinical focus is to identify individuals at risk BEFORE such consequences occurred. In addition to these philosophical differences, they also use body mass index (BMI) rather than waist
circumference to measure central obesity and introduce ethnicity as a risk factor.
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