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What Are the Symptoms of High Blood Sugar?
High blood sugar is also known as hyperglycemia. Left untreated, high blood sugar can be life threatening, leading to a diabetic coma. Watch for symptoms of high blood sugar so you can respond appropriately if you notice these signs of a problem.
What Is High Blood Sugar?
When blood sugar goes up, glucose rises in the bloodstream. This could happen for someone with diabetes, because the body isn’t utilizing glucose correctly.
When the body is using glucose correctly, it uses it to fuel the brain, other organs and muscles. Insulin produced by the pancreas is necessary to enable glucose to enter cells. If insulin isn’t present in the correct amounts, glucose will stay in the blood. This is when the blood sugar levels rise. Over time, blood vessels, nerves and organs are often damaged by high blood sugar.
Symptoms of High Blood Sugar
The symptoms of high blood sugar can be mild or severe. Sometimes people will live for years with mild symptoms, but they can also be so serious that you’ll know immediately when they happen.
The most common symptoms of high blood sugar include fatigue, increased thirst, frequent urination, blurred vision and headaches. Some people will also experience shortness of breath, stomach pain, nausea, vomiting, a rapid heart rate, a dry mouth and a fruity breath odor.
What to Do If You Notice Symptoms
If you think you’re having a blood sugar spike, you should check your blood sugar levels with a finger stick (if possible). If a high-carbohydrate meal has caused the spike, you might bring your sugar level down by drinking some water or exercising. When you exercise, you force your muscle cells to take in glucose, which removes it from the bloodstream. Getting regular exercise is an important part of an ongoing program for managing blood sugar levels.
Complications of High Blood Sugar
Left unchecked, high blood sugar could cause diabetic neuropathy, marked by tingling or numbness in the hands and feet. High blood sugar can cause circulation issues that slow down healing due to a lack of blood flow. This can cause minor sores to become infected, which could even lead to amputations. Blurred vision can happen from swollen lenses in the eyes, and changes the shape of lenses. Finally, a diabetic coma is life-threatening, possibly leading to brain damage and death.
Symptoms of Low Blood Sugar
Hypoglycemia is the medical word for low blood sugar. Symptoms of low blood sugar include anxiety, shakiness, nervousness, weakness, sweating, fatigue, nausea, dizziness, hunger, confusion and difficulty speaking. Sometimes blood sugar can drop quickly, giving you few warning signs that it’s happening. Low blood sugar demands treatment, just as high blood sugar does.
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4. Regulation of Blood Glucose
Regulation of glucose in the body is done autonomically and constantly throughout each minute of the day. Normal BG levels should be between 60 and 140 mg/dL in order to supply cells of the body with its required energy. Brain cells don’t require insulin to drive glucose into neurons; however, there must still be normal amounts available. Too little glucose, called hypoglycemia , starves cells, and too much glucose ( hyperglycemia ) creates a sticky, paralyzing effect on cells. Euglycemia, or blood sugar within the normal range, is naturally ideal for the body’s functions. A delicate balance between hormones of the pancreas, intestines, brain, and even adrenals is required to maintain normal BG levels.
Fuels of the Body
To appreciate the pathology of diabetes, it is important to understand how the body normally uses food for energy. Glucose, fats, and proteins are the foods that fuel the body. Knowing how the pancreatic, digestive, and intestinal hormones are involved in food metabolism can help you understand normal physiology and how problems develop with diabetes.
Throughout the body, cells use glucose as a source of immediate energy. To keep the body running smoothly, a continuous concentration of 60 to 100 mg/dL of glucose in blood plasma is needed. During exercise or stress the body needs a higher concentration because muscles require glucose for energy (Basu et al., 2009). Of the three fuels for the body, glucose is preferred because it produces both energy and water through the Krebs cycle and aerobic metabolism. The body can also use protein and fat; however, their breakdown creates ketoacids, making the body acidic, which is not its optimal state. Excess of ketoacids can produce metabolic acidosis.
Functioning body tissues continuously absorb glucose from the bloodstream. For people who do not have diabetes, a meal of carbohydrates replenishes the circulating blood glucose about 10 minutes after eating and continues until about 2 hours after eating. A first-phase release of insulin occurs about 5 minutes after a meal and a second phase begins at about 20 minutes. Because the duration of insulin’s effect is only about 2 hours, taking a 2-hour postprandial (after meal) BG shows how well insulin was released and used by the body. The food is broken down into small components including glucose and is then absorbed through the intestines into the bloodstream. Glucose (potential energy) that is not immediately used is stored by the body as glycogen in the muscles, liver, and fat.
Your body is designed to survive and so it stores energy efficiently, as fat. Most Americans have excess fat because they replenish the glucose stores by eating before any fat needs to be broken down.
When blood glucose levels fall after 2 hours, the liver replenishes the circulating blood glucose by releasing glycogen (stored glucose). Glycogen is a polysaccharide, made and stored primarily in the cells of the liver. Glycogen provides an energy reserve that can be quickly mobilized to meet a sudden need for glucose.
Hormones of the Pancreas
Regulation of blood glucose is largely done through the endocrine hormones of the pancreas, a beautiful balance of hormones achieved through a negative feedback loop. The main hormones of the pancreas that affect blood glucose include insulin, glucagon, somatostatin, and amylin.
Insulin (formed in pancreatic beta cells) lowers BG levels, whereas glucagon (from pancreatic alpha cells) elevates BG levels.
Somatostatin is formed in the delta cells of the pancreas and acts as the “pancreatic policeman,” balancing insulin and glucagon. It helps the pancreas alternate in turning on or turning off each opposing hormone.
Amylin is a hormone, made in a 1:100 ratio with insulin, that helps increase satiety , or satisfaction and state of fullness from a meal, to prevent overeating. It also helps slow the stomach contents from emptying too quickly, to avoid a quick spike in BG levels.
As a meal containing carbohydrates is eaten and digested, BG levels rise, and the pancreas turns on insulin production and turns off glucagon production. Glucose from the bloodstream enters liver cells, stimulating the action of several enzymes that convert the glucose to chains of glycogen—so long as both insulin and glucose remain plentiful. In this postprandial or “fed” state, the liver takes in more glucose from the blood than it releases. After a meal has been digested and BG levels begin to fall, insulin secretion drops and glycogen synthesis stops. When it is needed for energy, the liver breaks down glycogen and converts it to glucose for easy transport through the bloodstream to the cells of the body (Wikipedia, 2012a).
In a healthy liver, up to 10% of its total volume is used for glycogen stores. Skeletal muscle cells store about 1% of glycogen. The liver converts glycogen back to glucose when it is needed for energy and regulates the amount of glucose circulating between meals. Your liver is amazing in that it knows how much to store and keep, or break down and release, to maintain ideal plasma glucose levels. Imitation of this process is the goal of insulin therapy when glucose levels are managed externally. Basal–bolus dosing is used as clinicians attempt to replicate this normal cycle.
While a healthy body requires a minimum concentration of circulating glucose (60–100 mg/dl), high chronic concentrations cause health problems and are toxic:
- Acutely : Hyperglycemia of >300 mg/dl causes polyuria, resulting in dehydration. Profound hyperglycemia (>500 mg/dl) leads to confusion, cerebral edema, coma, and, eventually, death (Ferrante, 2007).
- Chronically : Hyperglycemia that averages more than 120 to 130 mg/dl gradually damages tissues throughout the body and makes a person more susceptible to infections. The glucose becomes syrupy in the bloodstream, intoxicating cells and competing with life-giving oxygen.
The concentration of glucose in the blood is determined by the balance between the rate of glucose entering and the rate of glucose leaving the circulation. These signals are delivered throughout the body by two pancreatic hormones, insulin and glucagon (Maitra, 2009). Optimal health requires that:
- When blood glucose concentrations are low, the liver is signaled to add glucose to the circulation.
- When blood glucose concentrations are high, the liver and the skeletal muscles are signaled to remove glucose from the circulation.
Test Your Knowledge
- A hormone produced in the pancreas.
- A polysaccharide that is stored in the liver.
- Produced in the striated muscles when exercising.
- An energy reserve that is slow to mobilize in an emergency.
Apply Your Knowledge
If you want to lose weight, what fuel would you decrease in your diet and what fuels would you increase?
The Role of Insulin
Insulin is a peptide hormone made in the beta cells of the pancreas that is central to regulating carbohydrate metabolism in the body (Wikipedia, 2016). After a meal, insulin is secreted into the bloodstream. When it reaches insulin-sensitive cells—liver cells, fat cells, and striated muscle—insulin stimulates them to take up and metabolize glucose. Insulin synthesis and release from beta cells is stimulated by rising concentrations of blood glucose. Insulin has a range of effects that can be categorized as anabolic , or growth-promoting.
- Is only available by injection or orally to treat T2DM.
- Is a hormone that acts on the liver to convert excess glucose into glycogen.
- Inhibits the uptake and use of glucose by skeletal muscles.
- Is manufactured and secreted by the alpha cells of the pancreas.
How would you explain the function of insulin to your patient with diabetes? What does it turn on and what does it turn off?
The Role of Glucagon
Glucagon , a peptide hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite to insulin, which lowers blood glucose levels. When it reaches the liver, glucagon stimulates glycolysis , the breakdown of glycogen, and the export of glucose into the circulation. In these ways, the effects of glucagon are catabolic , breaking down cells—the opposite of insulin’s anabolic effects (Drucker, 2008).
The pancreas releases glucagon when glucose levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. High BG levels stimulate the release of insulin. Insulin allows glucose to be taken up and used by insulin-dependent tissues, such as muscle cells. Glucagon and insulin work together automatically as a negative feedback system to keeps BG levels stable.
Glucagon is a powerful regulator of BG levels, and glucagon injections can be used to correct severe hypoglycemia. Glucose taken orally or parenterally can elevate plasma glucose levels within minutes, but exogenous glucagon injections are not glucose; a glucagon injection takes approximately 10 to 20 minutes to be absorbed by muscle cells into the bloodstream and circulated to the liver, there to trigger the breakdown of stored glycogen.
People with type 2 diabetes have excess glucagon secretion, which is a contributor to the chronic hyperglycemia of type 2 diabetes. The amazing balance of these two opposing hormones of glucagon and insulin is maintained by another pancreatic hormone called somatostatin , created in the delta cells. It truly is the great pancreatic policeman as it works to keep them balanced.
Complementary Roles of Insulin and Glucagon
After you’ve eaten, the concentration of glucose in your blood rises. When it goes too high the pancreas releases insulin into the bloodstream. This insulin stimulates the liver to convert the blood glucose into glycogen for storage. If the blood sugar goes too low, the pancreas release glucagon, which causes the liver to turn stored glycogen back into glucose and release it into the blood. Source: Google Images.
- Is a peptide hormone that is stored in the pancreas.
- Is used to treat hyperglycemia by increasing the uptake of glucose in muscles.
- Is a hormone that acts on the liver to convert glycogen back into glucose.
- Stimulates the production of insulin.
How is glucagon available by injection?
The Role of Amylin
Amylin is a peptide hormone that is secreted with insulin from the beta cells of the pancreas in a 1:100 ratio. Amylin inhibits glucagon secretion and therefore helps lower BG levels. It also delays gastric emptying after a meal to decrease a sudden spike in plasma BG levels; further, it increases brain satiety (satisfaction) to help someone feel full after a meal. This is a powerful hormone in what has been called the brain–meal connection.
People with type 1 diabetes have neither insulin nor amylin production. People with type 2 diabetes seem to make adequate amounts of amylin but often have problems with the intestinal incretin hormones that also regulate BG and satiety, causing them to feel hungry constantly. Amylin analogues have been created and are available through various pharmaceutical companies as a solution for disorders of this hormone.
The Role of Incretins
Incretins are glucagon-like peptides (hormones) made in cells of the small intestine and secreted into the circulation in response to food intake (Cernea & Raz, 2011). Incretins go to work even before blood glucose levels rise following a meal. They also slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying, and they may also help decrease food intake by increasing satiety.
People with type 2 diabetes have lower than normal levels of incretins, which may partly explain why many people with diabetes state they constantly feel hungry. After research showed that BG levels are influenced by intestinal hormones in addition to insulin and glucagon, incretin mimetics became a new class of medications to help balance BG levels in people who have diabetes.
Two types of incretin hormones are GLP-1 (glucagon-like peptide) and GIP (gastric inhibitory polypeptide). Each peptide is broken down by naturally occurring enzymes called DDP-4, (dipeptidyl peptidase-4).
Exenatide (Byetta), an injectable anti-diabetes drug, is categorized as a glucagon-like peptide (GLP-1) and directly mimics the glucose-lowering effects of natural incretins upon oral ingestion of carbohydrates. The administration of exenatide helps to reduce BG levels by mimicking the incretins. Both long- and short-acting forms of GLP-1 agents are currently being used.
The functions of incretins are as follows:
- Stimulate insulin secretion
- Suppress glucagon secretion
- Slow gastric emptying to prevent spike in BG levels
- Increase satiety after a meal to signal to the brain to stop eating
Incretins are deactivated quickly by enzymes called DPP-4, in the bloodstream and on the surface of endothelial cells; thus, the glucose-lowering effects of incretins last only a few minutes (Drucker & Nauck, 2006). A new class of medications, called DPP4 inhibitors, block this enzyme from breaking down incretins, thereby prolonging the positive incretin effects of glucose suppression. An additional class of medications called dipeptidyl peptidase-4 (DPP-4 inhibitors—note hyphen), are available in the form of several orally administered products. These agents will be discussed more fully later.
Incretins Stimulate Insulin Release
Source: Wikimedia Commons.
Poor Regulation of Blood Glucose
People with diabetes have frequent and persistent hyperglycemia, which is the hallmark sign of diabetes. For people with type 1 diabetes, who make no insulin, glucose remains in the blood plasma without the needed BG-lowering effect of insulin. Another contributor to this chronic hyperglycemia is the liver. When a person with diabetes is fasting, the liver secretes too much glucose, and it continues to secrete glucose even after the blood level reaches a normal range (Basu et al., 2009).
Another contributor to chronic hyperglycemia in diabetes is skeletal muscle. After a meal, the muscles in a person with diabetes take up too little glucose, leaving blood glucose levels elevated for extended periods (Basu et al., 2009).
The metabolic malfunctioning of the liver and skeletal muscles in type 2 diabetes results from a combination of insulin resistance, beta cell dysfunction, excess glucagon, and decreased incretins. These problems develop progressively.
Early in the disease the existing insulin resistance can be counteracted by excess insulin secretion from the beta cells of the pancreas, which try to address the hyperglycemia. The hyperglycemia caused by insulin resistance is met by hyperinsulinemia. Eventually, however, the beta cells begin to fail. Hyperglycemia can no longer be matched by excess insulin secretion, and the person develops clinical diabetes (Maitra, 2009).
People with type 2 diabetes have:
- Insulin sensitivity, which is an over-reaction of cells to insulin.
- No beta cells in their pancreas and no circulating insulin at all.
- Chronic hypoglycemia.
- Insulin resistance, which is a decreased response of cells to insulin.
How would you explain to your patient what lifestyle behaviors create insulin resistance?
The Problem of Insulin Resistance
In type 2 diabetes, many patients have body cells with a decreased response to insulin known as insulin resistance. This means that, for the same amount of circulating insulin, the skeletal muscles, liver, and adipose tissue take up and metabolize less glucose than normal. Being less sensitive to insulin, the liver does not react to the usual signal of insulin, so the liver manufactures and secretes more glucose than is needed (Huether & McCance, 2012).
Insulin resistance can develop in a person over many years before the appearance of type 2 diabetes. People inherit a propensity for developing insulin resistance, and other health problems can worsen the condition. For example, when skeletal muscle cells are bathed in excess free fatty acids, the cells preferentially use the fat for metabolism while taking up and using less glucose than normal, even when there is plenty of insulin available. In this way, high levels of blood lipids decrease the effectiveness of insulin; thus, high cholesterol and body fat, overweight and obesity increase insulin resistance.
Physical inactivity has a similar effect. Sedentary overweight and obese people accumulate triglycerides in their muscle cells. This causes the cells to use fat rather than glucose to produce muscular energy. Physical inactivity and obesity increase insulin resistance (Monnier et al., 2009).
The Problem of Beta Cell Dysfunction
For people with type 1 diabetes, no insulin is produced due to beta cells destruction. Research shows this is an autoimmune response gone awry, attacking the body’s own cells. Triggers of that autoimmune response have been linked to milk, vaccines, environmental triggers, viruses, and bacteria.
For people with type 2 diabetes, a progressive decrease in the concentration of insulin in the blood develops. The continuously decreasing availability of insulin in type 2 diabetes is the direct result of a progressive worsening of the beta cells’ ability to produce enough insulin when it is needed (Huether & McCance, 2012).
Not only do the beta cells release less insulin as type 2 diabetes progresses, they also release it slowly and in a different pattern than that of healthy people (Monnier et al., 2009). Without sufficient insulin, the glucose-absorbing tissues—mainly skeletal muscle, liver, and adipose tissue—do not efficiently clear excess glucose from the bloodstream, and the person suffers the damaging effects of toxic chronic hyperglycemia.
At first, the beta cells manage to manufacture and release sufficient insulin to compensate for the higher demands caused by insulin resistance. Eventually, however, the defective beta cells decrease their insulin production and can no longer meet the increased demand. At this point, the person has persistent hyperglycemia. In type 2 diabetes, beta cells seemingly exhaust their capacity to adapt to the long-term demands of peripheral insulin resistance (Huether & McCance, 2012).
A downward spiral follows. The hyperglycemia and hyperinsulinemia caused by the over-stressed beta cells create their own failure. In type 2 diabetes, the continual loss of functioning beta cells shows up as a progressive hyperglycemia.
In type 2 diabetes:
- Beta cells in the pancreas cannot compensate for insulin resistance.
- The pancreas is attacked by the body’s immune system, resulting in pancreatitis.
- The liver becomes overly sensitive to insulin.
- Glucose cannot be used as fuel by any cells in the body.
How would you explain insulin resistance differently to someone with type 1 diabetes and someone with type 2 diabetes?
Cell Damage in DM
Together, insulin resistance and decreased insulin secretion lead to hyperglycemia, which causes most of the health problems in diabetes. The acute health problems—diabetic ketoacidosis and hyperosmolar hyperglycemic state—are metabolic disorders that are directly caused by an overload of glucose. In comparison, the chronic health problems—eye, heart, kidney, nerve, and wound problems—are tissue injury, a slow and progressive cellular damage caused by feeding tissues too much glucose (ADA, 2015).
Hyperglycemic damage to tissues is the result of glucose toxicity. There are at least three distinct routes by which excess glucose injures tissues:
- Over time, excess glucose attaches to proteins in a process called glycosylation . For example, glycosylated hemoglobin (HbA1c), is the laboratory measure to monitor average glycemic levels. Glycosylated proteins trigger inflammatory reactions, which injure the lining of blood vessels. In addition, glycosylated proteins stick together on the basement membranes of capillaries, thickening the endothelial layers and disrupting their normal function.
- Excess intracellular glucose activates an enzyme called protein kinase C , which encourages the growth of unnecessary blood vessels, leads to blood vessel constriction, thickens basement membranes, and releases pro-inflammatory molecules such as C-reactive protein and homocysteine.
- Excess intracellular glucose reduces the effectiveness of the intracellular activities that protect against oxidants and oxidative stress. This leads to oxidative damage, especially in neurons. (Maitra, 2009)
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- Diabetes Type 2: Nothing Sweet About It Diabetes Type 2: Nothing Sweet About It 1. T2DM: A “Sweet” Walk Through Time 2. The Scope of Diabetes 3. Classification of Diabetes Mellitus 4. Regulation of Blood Glucose 5. Risk Factors for Diabetes Mellitus 6. Diagnosing Diabetes Mellitus 7. Prediabetes and Metabolic Syndrome 8. The Diabetes Healthcare Team 9. Treatment Strategies for Diabetes 10. Acute Complications of T2DM 11. Chronic Complications of T2DM 12. Prevention of Type 2 Diabetes 13. Summary and Resources 14. References / Quiz Login or Register
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- Exp Mol Med
- v.48(3); 2016 Mar
Pancreatic regulation of glucose homeostasis
Pia v röder.
1 Metabolism in Human Diseases Unit, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
2 Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore, Singapore
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.
The pancreas is an exocrine and endocrine organ
The pancreas has key roles in the regulation of macronutrient digestion and hence metabolism/energy homeostasis by releasing various digestive enzymes and pancreatic hormones. It is located behind the stomach within the left upper abdominal cavity and is partitioned into head, body and tail. The majority of this secretory organ consists of acinar—or exocrine—cells that secrete the pancreatic juice containing digestive enzymes, such as amylase, pancreatic lipase and trypsinogen, into the ducts, that is, the main pancreatic and the accessory pancreatic duct. In contrast, pancreatic hormones are released in an endocrine manner, that is, direct secretion into the blood stream. The endocrine cells are clustered together, thereby forming the so-called islets of Langerhans, which are small, island-like structures within the exocrine pancreatic tissue that account for only 1–2% of the entire organ ( Figure 1 ). 1 There are five different cell types releasing various hormones from the endocrine system: glucagon-producing α-cells, 2 which represent 15–20% of the total islet cells; amylin-, C-peptide- and insulin-producing β-cells, 2 which account for 65–80% of the total cells; pancreatic polypeptide (PP)-producing γ-cells, 3 which comprise 3–5% of the total islet cells; somatostatin-producing δ-cells, 2 which constitute 3–10% of the total cells; and ghrelin-producing ɛ-cells, 4 which comprise <1% of the total islet cells. Each of the hormones has distinct functions. Glucagon increases blood glucose levels, whereas insulin decreases them. 5 Somatostatin inhibits both, glucagon and insulin release, 6 whereas PP regulates the exocrine and endocrine secretion activity of the pancreas. 3 , 7 Altogether, these hormones regulate glucose homeostasis in vertebrates, as described in more detail below. Although the islets have a similar cellular composition among different species, that is, human, rat and mouse, their cytoarchitecture differs greatly. Although islets in rodents are primarily composed of β-cells located in the center with other cell types in the periphery, human islets exhibit interconnected α- and β-cells. 2 , 8
Anatomical organization of the pancreas. The exocrine function of the pancreas is mediated by acinar cells that secrete digestive enzymes into the upper small intestine via the pancreatic duct. Its endocrine function involves the secretion of various hormones from different cell types within the pancreatic islets of Langerhans. The micrograph shows the pancreatic islets. LM × 760 (Micrograph provided by the Regents of University of Michigan Medical School © 2012). Adapted from Human Anatomy and Physiology, an OpenStax College resource. 404
Through its various hormones, particularly glucagon and insulin, the pancreas maintains blood glucose levels within a very narrow range of 4–6 m M . This preservation is accomplished by the opposing and balanced actions of glucagon and insulin, referred to as glucose homeostasis. During sleep or in between meals, when blood glucose levels are low, glucagon is released from α-cells to promote hepatic glycogenolysis. In addition, glucagon drives hepatic and renal gluconeogenesis to increase endogenous blood glucose levels 9 during prolonged fasting. In contrast, insulin secretion from β-cells is stimulated by elevated exogenous glucose levels, such as those occurring after a meal. 10 After docking to its receptor on muscle and adipose tissue, insulin enables the insulin-dependent uptake of glucose into these tissues and hence lowers blood glucose levels by removing the exogenous glucose from the blood stream ( Figure 2 ). 11 , 12 , 13 Furthermore, insulin promotes glycogenesis, 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 lipogenesis 27 , 28 and the incorporation of amino acids into proteins; 29 thus, it is an anabolic hormone, in contrast to the catabolic activity of glucagon.
Maintenance of blood glucose levels by glucagon and insulin. When blood glucose levels are low, the pancreas secretes glucagon, which increases endogenous blood glucose levels through glycogenolysis. After a meal, when exogenous blood glucose levels are high, insulin is released to trigger glucose uptake into insulin-dependent muscle and adipose tissues as well as to promote glycogenesis.
The insulin secretion signaling pathway
Endocrine cells secrete their respective hormones in response to external signals, such as nutrient intake or stress, via humoral, neural or hormonal signaling pathways. The underlying molecular process that translates the stimulus into the actual hormone release is called stimulus-secretion coupling which is known as the stimulus-dependent exocytosis of a particular substance, such as glucose-stimulated β-cell insulin release. 30
In β-cells, the main stimulus for insulin release are elevated blood glucose levels following a meal. 10 The circulating blood glucose is taken up by the facilitative glucose transporter GLUT2 (SLC2A2), which is located on the surface of the β-cells. Once inside the cell, glucose undergoes glycolysis, thereby generating adenosine triphosphate (ATP), resulting in an increased ATP/ADP ratio. This altered ratio then leads to the closure of ATP-sensitive K + -channels (K ATP -channels). Under non-stimulated conditions, these channels are open to ensure the maintenance of the resting potential by transporting positively charged K + -ions down their concentration gradient out of the cell. Upon closure, the subsequent decrease in the magnitude of the outwardly directed K + -current elicits the depolarization of the membrane, followed by the opening of voltage-dependent Ca + -channels (VDCCs). The increase in intracellular calcium concentrations eventually triggers the fusion of insulin-containing granules with the membrane and the subsequent release of their content. 31 The whole secretory process is biphasic with the first phase peaking around 5 minutes after the glucose stimulus with the majority of insulin being released during this first phase. In the second, somewhat slower, phase, the remaining insulin is secreted. 32 , 33 , 34 Insulin is stored in large dense-core vesicles that are recruited to the proximity of the plasma membrane following stimulation such that insulin is readily available. 35 , 36 The key molecules that mediate the fusion of the insulin-containing large dense-core vesicles are the synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin-1 and synaptobrevin 2 (or vesicle-associated membrane protein VAMP2), all of which belong to the superfamily of the soluble N -ethylmaleimide-sensitive factor attachment protein (SNAP) receptor proteins (SNAREs). Together with the Sec1/Munc18-like (SM) proteins they form the so-called SNARE complex. 37 To initiate fusion, synaptobrevin 2, a vesicle (v-) SNARE that is integrated into the vesicle's membrane, fuses with the target (t-) SNAREs syntaxin-1 and SNAP-25, which are located in the target cell membrane, 38 , 39 with mammalian uncoordinated (munc)-18 playing a key regulatory role ( Figure 3 ). 40 , 41
Glucose-stimulated insulin release from a pancreatic β-cell. Exogenous glucose is taken up by GLUT2 and undergoes glycolysis inside the cell. Elevated adenosine triphosphate (ATP) levels alter the ATP/ADP ratio, which in turn leads to the closure of ATP-sensitive K + -channels. The subsequent membrane depolarization opens voltage-dependent Ca 2+ -channels in response to increasing intracellular calcium levels, which eventually trigger insulin secretion following vesicle fusion with the membrane.
To date, numerous SNARE isoforms, including syntaxin-1, -3 and -4, SNAP-25 and -23, as well as syntaptobrevins 2 and 3 (VAMP2 and 3), have been shown to be involved in glucose-stimulated insulin secretion, 42 , 43 , 44 , 45 , 46 whereas VAMP8, a non-essential SNARE protein for glucose-stimulated insulin secretion, has a role in the regulation of the glucagon-like peptide-1-potentiated insulin secretion. 47 In addition to SNARE and SM proteins, a calcium sensor is required for the initiation of membrane fusion. Synaptotagmins, which are highly expressed in neurons and endocrine cells, were shown to participate in Ca 2+ -dependent exocytosis processes. To date, 17 synaptotagmins (Syts 1–17) have been identified and only eight of them, namely Syt-1, -2, -3, -5, -6, -7, -9 and -10, are able to bind calcium. 48 Following Ca 2+ -binding, synaptotagmins form a complex with the SNAREs to facilitate and trigger the vesicle-membrane fusion process. Among the synaptotagmin family, Syt-3, -5, -7, -8 and -9 are implicated in insulin exocytosis. 49 , 50 , 51 , 52
External factors affecting pancreatic hormone secretion
The glucose-triggered stimulus-secretion coupling is an established paradigm of insulin secretion from β-cells and includes a great variety of modulators that trigger, potentiate or inhibit glucose-stimulated insulin secretion, primarily through G-protein-coupled receptors (GPCRs). The most traditional external factor that initiates insulin secretion is glucose. In addition to its trigger function, glucose also induces pathways that amplify insulin secretion through metabolism-cAMP (cyclic adenosine monophosphate) coupling or the incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). 31 Metabolism–cAMP coupling refers to the signaling cascade that occurs after the conversion of ATP, which is generated during intracellular glucose metabolism, into cAMP by adenylate cyclase (AC), 53 which in turn activates protein kinase A (PKA) 54 and cAMP-regulated guanine nucleotide exchange factors, also referred to as exchange protein directly activated by cAMP (Epac) 2. 55 , 56 Although Epac2 activation amplifies insulin secretion by mobilizing calcium from internal stores to increase Ca 2+ levels 57 , 58 and by controlling the granule density in proximity to the plasma membrane, 59 activated PKA exerts its effects by modulating K ATP -channel 60 , 61 and calcium channel 62 , 63 activity through phosphorylation, thereby enhancing the number of highly Ca 2+ -sensitive insulin-containing granules 64 and the probability of releasing secretory vesicles from the readily releasable pool, 65 respectively.
The incretins GLP-1 and GIP
The gut-derived hormones GLP-1 and GIP, which are secreted from enteroendocrine L-cells 66 and K-cells, 67 respectively, upon glucose, 66 , 68 fructose, 69 amino acid 70 and free fatty acid (FFA) 71 , 72 ingestion, also potentiate insulin release through the so-called incretin effect. This effect describes the observation that orally, but not intravenously, administered glucose enhances insulin secretion by triggering GLP-1 and GIP secretion; 73 , 74 , 75 the resulting potentiation of insulin secretion may account for up to 50% of the total release. The underlying mechanism includes GLP-1 and GIP binding to their GPCRs (GLP-1R and GIPR), both of which are expressed in pancreatic β-cells. 76 The binding induces a conformational change in the receptors' structure, followed by the exchange of guanosine diphosphate for guanosine triphosphate and the subsequent dissociation of the G s α-subunit from the receptors. This subunit, in turn, activates adenylate cyclase to convert ATP into cAMP, thereby stimulating the cAMP signaling pathway described above. 77 , 78 , 79 , 80 , 81 , 82 Furthermore, GLP-1 increases intracellular calcium concentrations by mobilizing Ca 2+ from ryanodine-sensitive stores 83 , 84 or, similar to GIP, by acting on voltage-dependent Ca 2+ -channels, 85 thereby potentiating insulin release. 85 , 86 , 87 Recent studies have also shown that GLP-1R agonists, such as exendin-4 88 , induce the PKA-mediated phosphorylation of Snapin or Synaptotagmin-7, which in turn enhances GSIS by Snapin interacting with SNAP-25 89 or by directly enhancing glucose- and Ca 2+ -triggered insulin release. 90
Free Fatty Acids
FFAs not only stimulate incretin secretion but are also known to modulate insulin release through fatty acid metabolism. Although long-chain FFAs augment insulin secretion, short-chain FFAs inhibit it. The binding and subsequent interaction of long-chain FFAs with the G-protein-coupled free fatty acid receptor (FFAR) 1 in the pancreatic β-cells leads to the activation of phospholipase C. PLC then hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP 2 ) to diacylglycerol and inositol-1,4,5-triphosphate (IP 3 ), with the latter docking on a calcium channel in the endoplasmic reticulum. The subsequent release of Ca 2+ into the cytosol increases the intracellular Ca 2+ concentration, which eventually triggers insulin secretion. 91 , 92 , 93 , 94 In contrast, short-chain FFAs inhibit glucose-stimulated insulin secretion due to decreased glucose oxidation and the subsequently decreased ATP/ADP ratio. 95 Another inhibitor of insulin release is stress, specifically norepinephrine (noradrenaline) produced in response to stress. 96 Norepinephrine binds to its α 2 -adrenergic receptors, which are linked to GPCRs, resulting in the inhibition of AC as well as in hyperpolarization. This prevents an increase in the cytosolic Ca 2+ concentration and, subsequently, insulin secretion. 97 , 98
Interplay between the pancreatic islets and other organs
The brain–islet axis.
Just as insulin exerts its effects on other organs and tissues, other organs interact with the pancreas to modulate insulin secretion ( Figure 4 ). One of these interacting organs is the brain, which comprises the mutual brain–islet axis that interacts with the pancreas and vice versa. The pancreas is highly innervated with both, parasympathetic 99 , 100 and sympathetic 100 , 101 nerve fibers from the autonomic nervous system. At the same time, insulin receptors are widely distributed within the brain, including the hypothalamus, cerebral cortex, cerebellum 102 and hippocampal formation 103 in humans, as well as the olfactory and limbic areas, 104 , 105 hypothalamus 106 —particularly the periventricular nucleus 107 and the arcuate nucleus 108 , 109 —hippocampus and the choroid plexus 105 in rat brains. Lesions in various brain regions were shown to affect pancreatic hormone secretion. The destruction of the ventromedial hypothalamus results not only in insulin hypersecretion 110 , 111 , 112 due to loss of the ventromedial hypothalamus-mediated inhibitory impact on pancreatic β-cells 113 but also in higher glucagon levels. 111 , 112 Glucagon secretion may also be modulated by the hypothalamic brain-derived neurotrophic factor 114 via efferent nerves, 115 whereas the melanocortin system directly reduces basal insulin levels by stimulating sympathetic nerve fibers via α-adrenoceptors. 116 Acting via α-adrenoceptors, 117 norepinephrine also inhibits insulin secretion, 96 which is an important aspect of the fight-or-flight response. The neurotransmitter Neuropeptide Y (NPY), which is mainly expressed in the sympathetic nerve fibers of the autonomic nervous system, also blunts insulin release, 118 , 119 and the loss of NPY's inhibitory action results in elevated basal and glucose-stimulated insulin secretion as well as in increased islet mass. 120 NPY binding to its GPCR Y 1 causes the activated G i α-subunit to block adenylate cyclase activation, which in turn inhibits the cAMP pathway. 121 Furthermore, the NPY-mediated inhibition was shown to be G βγ - and Ca 2+ -independent. 122 In addition to the well-known insulin stimulator acetylcholine, which exerts its effects via M 3 muscarinic receptors, 123 melanin concentrating hormone, vasoactive intestinal peptide (VIP), its close relative pituitary adenylate cyclase-activating polypeptide (PACAP) and gastrin-releasing peptide also promote insulin and, in the case of VIP 124 and PACAP, 125 glucagon release. The various neuropeptides exert their effects through various pathways, including the extracellular signal-regulated kinase (ERK)/Akt pathway, and modulation of Ca 2+ -influx (melanin concentrating hormone), 126 cAMP and, to a lesser extent, PI3K signaling (VIP and PACAP), 127 , 128 muscarinic/β-adrenoceptors signaling, PI3K/PKC signaling and Ca 2+ -mobilization from intracellular stores (gastrin-releasing peptide). 129 , 130
The interplay of the pancreas with the brain, liver, gut as well as adipose and muscle tissue. The pancreas interacts with the brain, liver, gut and adipose and muscle tissue in a highly sophisticated network via various hormones, neurotransmitters and cytokines. BNDF, brain-derived neurotrophic factor; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GRP, gastrin-releasing peptide; IL-6, Interleukin 6; MCH, melanin concentrating hormone; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; POMC, pro-opiomelanocortin; VIP, vasoactive intestinal peptide.
Likewise, insulin release is stimulated by the so-called cephalic phase, which represents the conditioned reflex of increased hormone secretion, referred to as cephalic phase insulin response, 131 even in the absence of nutrients/glucose as a trigger, 132 , 133 , 134 such as when anticipating a meal, to prepare the organism to adequately respond to incoming nutrients. 135 Moreover, cephalic phase insulin response is pivotal for ensuring normal postprandial glucose management. 136 The neural mechanism underlying cephalic phase insulin response was found to include cholinergic and non-cholinergic processes 136 as well as the dorsal vagal complex located in the medulla oblongata. 137 Conversely, insulin released in response to a meal enters the brain via the blood–brain–barrier 138 to decrease food intake 139 , 140 by stimulating hypothalamic pro-opiomelanocortin neurons 141 and initiating the PI3K signaling pathway 142 in these pro-opiomelanocortin neurons. 143 In contrast to its pro-opiomelanocortin-stimulating action, insulin inhibits NPY expression 144 in Agouti-related peptide (AgRP/NPY) neurons, which are known to secrete the orexigenic neuropeptides NPY 145 , 146 , 147 and AgRP. 148 , 149 Both, peripheral and central insulin signaling are impaired in obese or diabetic states. 150 , 151 , 152 , 153 , 154
The liver–islet axis
The second group represents the liver–islet axis. The liver has a key role in glucose homeostasis by storing (glycogenesis) or releasing (glycogenolysis/gluconeogenesis) glucose upon interaction with insulin and glucagon, respectively. The binding of glucagon to its hepatic GPCR evokes the signaling cascade described under ‘External factors affecting pancreatic hormone secretion', eventually resulting in the activation of PKA, which in turn stimulates two processes; one promotes glycogenolysis/gluconeogenesis and the other inhibits glycolysis/glycogenesis. 155 , 156 Glycogenolysis is a multistep process that includes the PKA-mediated phosphorylation of phosphorylase kinase, 157 cleavage of glucose-1-phosphate (G-1-P) from glycogen by activated glycogen phosphorylase a 158 and the conversion of G-1-P into G-6-P, 159 eventually resulting in phosphate and free glucose. Hepatic gluconeogenesis is promoted by the PKA-mediated phosphorylation of the cAMP response element-binding protein, which in turn upregulates peroxisome proliferator-activated receptor-γ coactivator (PGC)-1. 160 Together with the hepatocyte nuclear factor (HNF)-4, PGC-1 induces the transcription of phosphoenolpyruvate carboxykinase, 161 which catalyzes the conversion of oxaloacetate into phosphoenolpyruvate, a rate-limiting step in gluconeogenesis. This is followed by reversed glycolysis, during which stimulation of the bifunctional PFK-2/FBPase-2 leads to both, enhanced gluconeogenesis through the abrogation of disabled fructose-1,6-bisphosphatase (FBPase)-1, which facilitates the successive conversion of substrates into G-6-P, and to suppressed glycolysis. 162 , 163 Glycolysis is further inhibited by the PKA-mediated inactivation of pyruvate kinase, 164 , 165 , 166 resulting in the production of glucose instead of pyruvate. In addition, glucagon was found to suppress pyruvate kinase gene expression as well as to enhance pyruvate kinase mRNA degradation. 167 , 168 Finally, the PKA-induced inactivation of hepatic glycogen synthase 169 , 170 , 171 decreases glycogen synthesis and concomitantly increases the hepatic glucose pool.
As glucagon's opponent, insulin stimulates glycolysis via enhanced expression of the hepatic glucokinase gene, 14 , 15 a key enzyme that converts glucose into G-6-P. This increase is mediated by the sterol regulatory element binding protein-1c 15 and requires the absence of cAMP. 14 Furthermore, insulin inactivates glycogen phosphorylase and glycogen synthase kinase (GSK)-3 172 through the PI3K pathway, which in turn activates glycogen synthase. 18 , 19 , 20 The second liver-specific effect of insulin is to repress the expression of the phosphoenolpyruvate carboxykinase and G-6-Pase genes; the first by disrupting the association of cAMP response element-binding protein and RNA polymerase II with the phosphoenolpyruvate carboxykinase gene promoter, 23 whereas G-6-P suppression requires PKBα/Akt and forkhead transcription factor (FOXO1), 24 , 25 whose expression was shown to be diminished by the inhibition of GSK-3. 26
It is not only insulin and glucagon acting on the liver; hepatocyte-derived factors conversely influence the pancreas and/or insulin secretion. Although HNF3β was proposed to be pivotal for the transcription of the pancreatic and duodenal homeobox 1 (pdx1 or insulin promotor factor 1 (IPF-1)) gene, a transcription factor regulating pancreatic development 173 , 174 , 175 , it is the loss of HNF1α resulting in an almost abolished insulin secretion, likely due to a decreased response to intracellular calcium. These findings support the importance of HNF1α in maintaining β-cell function 176 and its involvement in maturity-onset diabetes of the young (MODY3). 177
The hepatokine betatrophin, also known as TD26, re-feeding induced fat and liver (RIFL), lipasin or angiopoietin-like (ANGPTL) 8, was first identified as a factor that drives β-cell proliferation and thus increases β-cell mass in a murine model of insulin resistance. 178 Subsequent studies, however, did not reveal impairments in glucose homeostasis 179 or β-cell expansion in Angptl8 knockout mice. 180 Moreover, betatrophin does not have an effect on human β-cell replication, challenging its usefulness in diabetes therapy. 181 This is substantiated by the fact that betatrophin levels are higher in T2DM patients, 182 , 183 , 184 although they were lower in one study. 185 However, this is likely to be due to technical issues. 186
The gut–islet axis
Another important axis is the gut–islet axis. The gut releases various hormones upon nutrient ingestion, including GLP-1 and GIP, that bind to their respective receptors on pancreatic β-cells to potentiate insulin secretion, as described under ‘External factors affecting pancreatic hormone secretion'. Furthermore, both hormones exert pancreatic effects, such as GLP-1-stimulated insulin gene expression, 77 , 187 incretin-induced β-cell neogenesis, proliferation 188 , 189 , 190 , 191 and survival, 192 the prevention of β-cell apoptosis in general 193 , 194 and in response to glucolipotoxicity. 195 The extrapancreatic actions of GLP-1 include suppression of endogenous glucose production 196 /glycogenolysis, 197 glucagon secretion, 197 , 198 appetite, 199 , 200 a delay in gastric emptying 198 , 199 and improved β-cell insulin sensitivity 199 , 201 , 202 and glucose disposal, 203 , 204 whereas GIP positively affects lipid 205 , 206 , 207 and bone metabolism. 208 , 209 , 210 , 211 Thus, GLP-1 and GIP mediate insulin secretion and concomitantly, insulin modulates GIP 212 and GLP-1 release; the latter ocurring through the PI3K/Akt- and mitogen-activated protein kinase kinase (MAPKK or MEK)/ERK1/2 pathway. 213 The importance of this interplay is also demonstrated by defective insulin responses and consequent glucose intolerance in GLP-1R −/− and GIPR −/− mice 214 , 215 , 216 , 217 , 218 as well as in the pathogenesis of T2DM. 219 , 220 , 221 , 222 , 223
In addition to incretins, there are the so-called decretins, namely limostatin and Neuromedin U (NmU), which are secreted during fasting to suppress insulin release. NmU, a (neuro)peptide that mediates the contraction of smooth muscles in the uterus (hence the ‘U') among others, was first isolated from the pig spinal cord. 224 Further mRNA expression studies, however, revealed NmU to be highly expressed in the gastrointestinal (GI) tract with the highest levels found in the upper GI, that is, duodenum and jejunum. 225 , 226 Within the GI structure, NmU is mainly located in submucosal and myenteric cells, 227 , 228 indicating its possible involvement in the neuronal control of GI function. 229 In addition to this, NmU is likely to regulate insulin secretion; the G-protein-coupled NmU receptor 1 (NmUR1) is expressed in pancreatic islets and its simulation dose dependently decreased insulin release. 230 , 231 The underlying mechanism involves the simultaneous release of somatostatin—a known modulator of insulin secretion 6 —upon NmUR1 activation. 232 A very recent study showed 231 that the peptide hormone limostatin, which is expressed in Drosophila melanogaster, also reduces insulin secretion and its absence caused hyperinsulinemia, hypoglycemia and obesity. Moreover, knockdown of the fly NmUR orthologue not only reproduced the consequences of limostatin deficiency but also diminished its insulin-suppressing ability. Limostatin release is initiated by food depletion and hence may represent a novel mechanism for modulating insulin secretion during fasting.
Other gastrointestinal hormones that interact with the pancreas are gastrin and cholecystokinin (CCK). Gastrin, which is secreted from G-cells in the stomach and duodenum, acts as an islet growth factor, together with transforming growth factor-α, by promoting differentiation of ductular precursor cells 233 and β-cell neogenesis as well as by enhancing the islet mass from transdifferentiated exocrine pancreatic tissue. 234 Furthermore, it induces the expression of glucagon genes in α-cells. 235 Along the same lines, CCK, which is synthesized and released from duodenal I-cells, potentiates basal, glucose- 236 , 237 and amino acid-induced insulin secretion, 238 and augments glucagon secretion. 237 , 239 The pivotal role of CCK in modulating glucose homeostasis is reflected in postprandial hyperglycemia, which is due to reduced CCK plasma levels in noninsulin-dependent diabetes mellitus. 240
Another important factor that is related to metabolic disorders such as obesity, T2DM and type 1 DM (T1DM) is the gut microbiota. Obesity, T2DM and T1DM patients display alterations in the composition of their microbiota that may initiate and/or promote the respective disorder. Recent findings linked an aberrant microbiome, which is generally represented by diminished diversity, including fewer butyrate-producing (butyrate was shown to trigger mucin production and hence gut integrity) and mucin-degrading bacteria, 241 to the development of autoimmunity in T1DM. 242 An altered microbiota composition may also contribute to obesity 243 , 244 as well as to T2DM 245 , 246 , 247 and ‘correction' by antibiotics, 248 probiotics 249 or prebiotics, the last of which causing a short-chain FFA-stimulated increase in GLP-1, 250 may improve the disease condition. 251
The adipocytes/myocytes–islet axis
On one hand, insulin's interplay with adipose and muscle tissues is broadly based on facilitating insulin-dependent glucose uptake through the glucose transporter 4 (GLUT4). 11 , 12 , 13 On the other hand, adipokines and myokines secreted from the adipose and muscle tissue, respectively, modulate insulin release. As part of the so-called adipoinsular axis, 252 leptin, the most famous adipokine, mainly acts on its receptors in the hypothalamic arcuate nucleus to inhibit food intake and control whole body homeostasis. 253 However, leptin receptor (Ob-R) mRNA expression was also observed in pancreatic islets 254 and its stimulation caused a reduction in insulin secretion 255 , 256 , 257 due to the activation of K ATP -channels, which in turn prevented Ca 2+ -influx 258 and the subsequent signaling pathway. Furthermore, leptin was shown to suppress insulin gene expression, 259 , 260 representing a negative feedback loop. Conversely, insulin enhances ob gene expression and leptin secretion. 261 , 262 , 263 , 264 Likewise, insulin modulates the expression of adiponectin, another well-known adipokine, the abundance of its receptor in adipose and muscle tissue 265 , 266 as well as its secretion. 267 , 268 Adiponectin is not only involved in glucose and fatty acid metabolism 269 but it also forestalls β-cell apoptosis and induces insulin gene expression and release; 270 the latter was mediated by the ERK/Akt pathway in one study 270 and by the AMPK pathway in another study. 271 Other adipokines, such as apelin, 272 , 273 chemerin, 274 , 275 , 276 omentin, 277 , 278 resistin 279 and visfatin, 280 , 281 were also shown to directly interact with insulin, whereas retinol-binding protein 4, tumor necrosis factor-α and vaspin are related to insulin in an indirect manner. 282 In addition to adipokine secretion by adipocytes, myocytes release cytokines, which are referred to as myokines. Fibroblast growth factor-21 is a widely expressed protein with a broad mode of action, including the regulation of carbohydrate and fatty acid metabolism 283 and may be considered as a myokine due to its secretion from muscle cells. 284 Fibroblast growth factor-21 is regulated by insulin 285 through the PI3K/Akt1 signaling pathway. 286 Interleukin (IL)-6, which is both an adipokine and myokine, 287 was shown to influence the pancreas by controlling the expression of pro-glucagon mRNA as well as glucagon secretion. It also increases α-cell proliferation and islet mass while protecting the pancreas from metabolic stress-induced apoptosis. 288 Furthermore, IL-6 increased GLP-1 production from proglucagon in pancreatic α-cells and its secretion from α-cells and intestinal L-cells, eventually resulting in a GLP-1-mediated increase in insulin secretion. 289
Modulating insulin secretion as a means of diabetes therapy
Due to the worldwide, still spreading epidemic of T2DM, there is an urgent need for (new) anti-diabetic drugs and therapies that are more effective and have fewer side effects. Currently, the most commonly used drugs can be classified into agents that enhance insulin secretion (secretagogues such as sulfonylureas (SUs) and incretin mimetics), sensitize the target organs of insulin (for example, metformin from the class of biguanides or thiazolidinediones), or reduce glucose absorption from the gastrointestinal tract (inhibitors of gastrointestinal α-glucosidase). Different therapies address different problems and stages of T2DM and may be prescribed in combination to exert synergistic effects.
A-glucosidase inhibitors and sensitizers do not target the pancreas or insulin secretion itself but instead target the upstream (slowed intestinal glucose absorption) or downstream (improved insulin sensitivity) processes. In contrast, insulin secretagogues directly modulate insulin release. The SUs are the first broadly applied oral anti-hyperglycemic drugs. To date, there are two generations of agents: acetohexamide, chlorpropamide, tolazamide and tolbutamide, which constitute the first generation and glibenclamide/glyburide, gliclazide, glimepiride, glipizide and gliquidone, which comprise the second generation. First-generation SUs are rarely used these days since tolbutamide intake was associated with an increase in lethal cardiac events. 290 , 291 More importantly, the second-generation SUs are more potent due to modifications in their side chains' structure, resulting in improved SUR-affinity, accompanied by lower effective plasma levels, which in turn may reduce undesirable drug-protein interactions.
All SUs share a central SU backbone but differ in their side chains. Despite having different pharmacokinetics, they work in the same way, namely by triggering endogenous insulin release by blocking K ATP -channels and hence activating the insulin signaling pathway. More precisely, SUs bind to the sulfonylurea receptor (SUR) subunit of the K ATP -channel with high affinity. 292 , 293 SUR, together with the pore-forming subunit Kir6.x, forms a hetero–octameric complex consisting of four inner Kir6.x subunits surrounded by four SUR subunits (4:4 stoichiometry). 294 , 295 Moreover, different isoforms of the two subunits are expressed, depending on the tissue-specific expression of the K ATP -channels: SUR1 and Kir6.2 are expressed in the pancreas and brain, 296 Kir6.2 and SUR2A are expressed in the heart and skeletal muscle, 297 while SUR2B is expressed in the brain and smooth muscle, 298 and Kir6.1 and SUR2B are expressed in vascular smooth muscle. 299 Although SUs bind to both, SURs and Kir6.2, the interactions with the latter are of low affinity 300 , 301 and hence only SUR-interacting agents are used for diabetes treatment. In addition to their mode of action as inhibitors of K ATP -channels, SUs were shown to improve glucose uptake into insulin-dependent tissues and glucose disposal as well as to reduce hepatic glycogenolysis/gluconeogenesis. 302 , 303 , 304
In contrast to SUs inactivating the K ATP -channels by binding to the SUR1 subunit, ATP closes them by interacting with Kir6.2. 305 Moreover, while the binding of only one ATP molecule is sufficient to completely close the channel, 306 inhibition by SUs is incomplete as the channel might still open even when SUs are bound to SUR1. 299 Nonetheless, second-generation SUs reduce the glycated hemoglobin or HbA 1c , which represent the average plasma glucose concentrations over time and thus serve as a diagnostic measure for diabetes mellitus, by 1.0–2.0%. In addition to the weight gain attributed to the anabolic effects of increased insulin secretion, the main side effect of SUs is hypoglycemia 307 , 308 due to excess circulating insulin levels and due to the fact that SUs evoke insulin secretion in a glucose-independent manner. 309
Although they are not SUs per se , meglitinides, that is, repaglinide and nateglinide, share their mode of action of inhibiting K ATP -channels. 310 However, meglitinides and some of the second-generation SUs, for example, glibenclamide, interact with both, the SUR1 and the SUR2A or B isoforms. 311 Despite the possible disadvantage of this generalized binding that may cause undesirable effects on other K ATP -channel types, for example, those in the heart, 312 meglitinides, namely nateglinide, have an earlier onset of action and a faster dissociation rate from the sulfonylurea receptor, 313 , 314 , 315 resulting in a diminished risk of hypoglycemia. 316 Like SUs, meglitinides also cause weight gain. 317 , 318
Another group of insulin secretagogues is comprised of the incretins GLP-1 and GIP. As both incretins are rapidly inactivated by the enzyme dipeptidyl peptidase IV (DPP-IV), 319 their application in T2DM treatment focuses on modified analogues 320 , 321 , 322 , 323 , 324 , 325 or receptor agonists, including the well-known, short-acting exenatide. 326 , 327 , 328 The long-lasting agonists exenatide LAR, 329 , 330 liraglutide 331 , 332 and lixisenatide 333 , 334 , 335 are currently under investigation. However, based on the lipogenetic properties 205 , 206 , 207 of GIP, insufficient insulin-potentiating effects in T2DM patients 220 , 336 and a possible worsening effect by GIP, 337 , 338 the focus is on GLP-1 analogues/receptor agonists for T2DM treatment. By acting on its receptor, GLP-1 induces the signaling cascade described under ‘External factors affecting pancreatic hormone secretion', resulting in its main effect: potentiating insulin secretion. In addition to reducing the HbA 1C levels, GLP-1 analogues/receptor agonists promote weight loss and, more importantly, do not evoke hypoglycemia, as do SUs, 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 due to the glucose-dependent mode of action and the self-regulating mechanism of GLP-1. 68 , 336 , 339 When blood glucose levels are lowered to physiological levels, GLP-1 is incapable of enhancing insulin secretion, thereby preventing hypoglycemia. 79 , 340 In addition, GLP-1 (analogues/receptor agonists) exerts further pancreatic and extrapancreatic actions, as mentioned under ‘Interplay between the pancreatic islets and other organs'. Although GLP-1 (analogues/receptor agonists) exhibits some minor side effects, including nausea, vomiting or gastrointestinal impairments, 326 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 , 335 the beneficial properties outweigh the negative effects, and thus, GLP-1 is a promising anti-diabetic agent.
Metformin, which is generally the most widely used first-line anti-diabetic medication, 341 is a so-called (insulin) sensitizer. It not only diminishes hepatic glucose output due to glycogenolysis/gluconeogenesis 342 but it also enhances glucose uptake into peripheral tissues, such as skeletal muscle, by activating 5′-adenosine monophosphate-activated protein kinase (AMPK-α2). 343 Furthermore, it supports weight loss 344 by reducing food consumption. 345 With respect to its effects on β-cell function, metformin was shown to increase insulin gene expression, 346 possibly by nuclear accumulation of pdx1 and its subsequently improved DNA-binding activity. 347 Interestingly, metformin exerts opposing effects on β-cell proliferation and/or apoptosis; on the one hand, it suppresses β-cell proliferation and enhances apoptosis through an AMPK-dependent and autophagy-mediated mechanism 348 following the metformin-induced activation of c-Jun-N-terminal kinase and caspase-3. 349 On the other hand, metformin reduces caspase-3- and -8-mediated apoptosis in isolated islets from T2DM patients 350 and protects against lipotoxicity-induced β-cell defects. 348 , 351
The other members of the sensitizer group include the thiazolidinediones (or glitazones). Currently, only pioglitazone is available; troglitazone was withdrawn from the market in 2000 and rosiglitazone was withdrawn in 2010 due to liver toxicity, drug-induced hepatitis 352 , 353 , 354 and the increased risk of cardiovascular events, respectively. 355 Their mode of action involves activation of the peroxisome proliferator-activated receptor (PPARγ), a nuclear transcription factor that is highly expressed in adipose tissue, and the subsequent regulation of genes that are involved in glucose and fat metabolism. 356 , 357 , 358 By promoting lipogenesis, FFAs are removed from the blood stream, whereupon cells become dependent on glucose as an energy substrate. However, enhanced lipogenesis also leads to the weight gain observed in thiazolidinedione-treated T2DM patients. 359 In contrast to metformin, pioglitazone prevents (oxidative stress-induced) apoptosis 360 , 361 by decreasing the expression of apoptosis-promoting genes, while increasing anti-apoptotic and anti-oxidative gene expression. However, this may depend on the disease state. 362 , 363 Furthermore, pioglitazone increases β-cell mass by upregulating cell differentiation/proliferation genes. 364 Although they have partially different modes of action, both groups of sensitizers cause a reduction in the HbA 1c level by 1.5–2.0%.
A-glucosidase inhibitors, such as acarbose, miglitol and voglibose, not only decelerate the breakdown of starch into glucose in the small intestine but also decrease its bioavailability, resulting in reduced levels of glucose entering the blood stream and hence attenuated postprandial glucose excursions. 365 , 366 , 367 , 368 , 369 , 370 In addition, they support weight loss 371 , 372 and ameliorate blood pressure, 373 insulin sensitivity 367 , 368 and triglyceride levels. 369 , 370 Similar to pioglitazone, α-glucosidase inhibitors attenuate reductions in β-cell mass, which may delay the onset of diabetes. 374 , 375 , 376 As α-glucosidase inhibitors only mildly reduce HbA 1c levels (0.5–1.0%), they are usually only used in the early stage of T2DM, that is, impaired glucose tolerance or in combination with other drugs. 377
Conclusions and outlook
The pancreas has key roles in maintaining normal blood glucose levels by producing and releasing insulin and glucagon. These opponents interact not only with each other through the intra-islet insulin axis 378 , 379 , 380 , 381 but also with other organs/tissues, that is, the brain, liver, gut as well as insulin-dependent adipose and muscle tissues. Altogether, the islet–organ/tissues axes described here form a highly sophisticated network that includes, but is not limited to, various signaling molecules, that is, neuropeptides (brain-derived neurotrophic factor, NPY, melanin concentrating hormone, gastrin-releasing peptide, VIP and PACAP), hepatokines (betatrophin and HNFs), enteroendocrine hormones (the incretins GLP-1 and GIP, the decretins NmU and limostatin, gastrin and CCK) as well as adipokines (leptin and adiponectin) and myokines (fibroblast growth factor-21 and IL-6) that mainly interact through GPCR signaling pathways, such as the cAMP cascade. In good health, the well-functioning interactions between all of the organs and tissues involved ensure glucose homeostasis. However, impairments in the secretion of and/or sensitivity to insulin may result in metabolic diseases, such as T2DM. Referring to the American Diabetes Association, T2DM and noninsulin-dependent diabetes mellitus are characterized by insulin resistance, hyperglycemia and a relative insulin deficiency. Furthermore, T2DM is associated with low-grade inflammation, 382 , 383 cardiovascular disease, 384 , 385 nephropathy 386 , 387 and alterations in the secretion of various hormones, including IL-6, IL-18, tumor necrosis factor-α, 388 adiponectin and leptin, 389 neuropeptides, 390 ghrelin 391 , 392 and the incretins GLP-1 and GIP. 219 , 220 , 221 , 222 , 223 Although lifestyle interventions 393 and weight loss 394 reverse T2DM in early stages, when insulin is still secreted, T2DM patients may become dependent on anti-diabetic drugs in later stages. Currently, there are three classes of agents: insulin secretatogues, insulin sensitizers and α-glucosidase inhibitors, all of which have different modes of action and hence target different stages and symptoms of T2DM. Treatments that modulate insulin release—on condition of an appropriate insulin sensitivity of the target organs—appear to be promising approaches. Current research is unveiling new molecules, enzymes and interactions that are involved in the signaling pathways underlying insulin secretion, among others, and is likely to introduce new therapeutic approaches. Strategies that target these mediating molecules may include, but are not limited to, the calcium sensor Syt-7, 90 , 395 the SNARE-associated protein Snapin, 89 the t -SNARE SNAP-25, 396 cyclin-dependent kinase (Cdk) 5, 397 ryanodine receptor (RyR) 2, 398 the nucleotide exchange factor and intracellular cAMP sensor Epac2, 57 , 58 , 59 , 399 mammalian uncoordinated proteins (munc)13 400 , 401 and munc18 40 , 41 as well as the Ras-related proteins (Rab) 3A 402 and 27A. 403
The authors declare no conflict of interest.
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