Incretins And The Regulation Of Insulin Secretion
Insulin secretion in response to orally administered glucose and other nutrients is 25% to 50% greater than that after their intravenous administration . This so-called incretin effect is mediated by hormones released from the gutprimarily GIP and GLP-1 . GIP is produced by K cells in the duodenum and upper jejunum, and it is released into the circulation after ingestion of nutrients. GLP-1 is synthesized in enteroglucagon or L cells, which also contain peptide YY and enteroglucagon. These L cells are primarily located in the distal small bowel, colon, and rectum. Of these two hormones, GIP is probably the major physiologic incretin. Glucose and amino acids are considered to be primary and direct stimulants of insulin secretion, but insulin secretion also is modulated by the incretins. They cause little or no insulin release in the absence of glucose or amino acids, but they can alter insulin release dramatically in response to either glucose or amino acids.
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Regulation Of Insulin Translation
In response to nutrients, -cells enhance their overall speed of protein translation, which is at least partly controlled by dephosphorylation of eukaryotic initiation factor 2a via protein phosphatase 1 . For example, exposure of -cells to high glucose for 2 hours significantly decreases the ratio of phosphorylated eIF2a to eIF2a . However, there are additional mechanisms to regulate glucose-induced insulin translation, since the overall protein translation induced by glucose compared to the fasting state in -cells was only 3-fold compared with an up to 8-fold induction in proinsulin translation .
Sites Of Insulin Action And Manifestations Of Insulin Resistance
The effects of insulin, insulin deficiency and insulin resistance vary according to the physiological function of the tissues and organs concerned, and their dependence on insulin for metabolic processes. Those tissues defined as insulin dependent, based on intracellular glucose transport, are principally adipose tissue and muscle. However, insulins actions are pleotropic and widespread, as are the manifestations of insulin resistance and the associated compensatory hyperinsulinaemia.3
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High Calorie Foods May Or May Not Cause The Blood Sugar Level To Rise
Many people think that all high-calorie foods raise blood sugar level, but this is not always the case.
In general, foods that cause blood sugar level to rise the most are those that are high in carbohydrates, which are quickly converted into energy, such as rice, bread, fruits and sugar. Next are foods high in protein, such as meats, fish eggs, milk and dairy products, and oily foods. However, even though carbohydrates affect blood sugar levels, if you don’t eat them your diet will be unbalanced and you won’t feel satisfied after your meal, which can lead to excessive consumption of foods rich in protein and fat.
Food containing three major nutrients
Prevention Of Insulin Resistance
Making lifestyle changes can help reverse insulin resistance so that your body can respond properly to insulin.
Lose weight.Eat a .
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The Link Between The Gut And The Pancreas
Insulin is produced in higher amounts when sugar passes through the gut compared to when glucose is injected into the veins . This is because when sugar enters the gut, messages are sent from the gut to the pancreas to produce more insulin. These messages are chemicals called peptides. The best known gut peptide controlling insulin is called GLP1 . GLP1 speaks to the pancreas after glucose enters the gut, telling it to produce insulin at the right time. It is now known that in type 2 diabetes, GLP1 levels are too low, which is partly why blood sugar levels go too high after a meal . There are now many medicines that increase GLP1 levels to control post-prandial hyperglycaemia which are therefore good treatments for type 2 diabetes.
Last reviewed: Jul 2022
The Discovery Of Insulin
In 1889 German scientists Minkowski and von Mering noted, from their experimental work with animals, that total pancreatectomy led to the development of severe diabetes.4 They hypothesised that a substance secreted by the pancreas was responsible for metabolic control. Others later refined this hypothesis, noting diabetes to be associated with destruction of the islets of Langerhans. While Minkowski, as well as Zuelzer in Germany and Scott in the USA attempted, with inconsistent results, to isolate and administer the missing pancreatic islet substance, Belgian investigator de Meyer in 1909 proposed the name insuline, as did British researcher Schaefer in 1916.
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What Happens If Insulin Does Not Work Properly
If insulin does not work properly on its receptor it may lead to type 2 diabetes. Type 2 diabetes can be caused by two main factors and its severity will depend on how advanced the problems are. Firstly, the patients beta cells may have problems manufacturing insulin, so although some insulin is produced, it is not enough for the bodys needs. This is relative insulin deficiency rather than the absolute insulin deficiency that is seen in type 1 diabetes. Secondly, the available insulin doesnt work properly because the areas in the cell where insulin acts, called insulin receptors, become insensitive and stop responding to the insulin in the bloodstream. This is called insulin resistance and is very common in obesity and type 2 diabetes. These receptors appear to malfunction more in people who carry excessive amount of weight. Some people with type 2 diabetes might initially experience very few symptoms and the raised blood glucose is only picked up when a routine blood test is arranged for another reason other people might experience symptoms similar to those seen in patients with type 1 diabetes . Some patients with type 2 diabetes can control their symptoms by improving their diet and/or losing weight, some will need tablets, and others will need to inject insulin to improve blood glucose levels. See the article on diabetes mellitus for more information.
Measurement Of Insulin And Insulin Resistance
There are a variety of approaches to the laboratory assessment of insulin resistance. Over the years the limited specificity of older radio-immunoassays that cross-react with proinsulin have reduced the credibility of measuring insulin resistance in clinical settings. Current assays have improved specificity and precision. A comprehensive review of insulin assays is beyond the scope of this review and the reader is encouraged to consult Sapin128 in this regard. Insulin resistance may be measured by looking directly at insulin mediated glucose uptake in the basal or post-stimulated state, by inference from the relative concentrations of glucose and insulin, or by looking at surrogate markers of insulin action.
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Mechanisms Of Insulin Secretion
Increased levels of glucose induce the first phase of glucose-mediated insulin secretion by release of insulin from secretory granules in the cell. Glucose entry into the cell is sensed by glucokinase, which phosphorylates glucose to glucose-6-phosphate , generating ATP.12 Closure of K+-ATP-dependent channels results in membrane depolarization and activation of voltage dependent calcium channels leading to an increase in intracellular calcium concentration this triggers pulsatile insulin secretion.13 Augmentation of this response occurs by both a K+-ATP channel-independent Ca2+-dependent pathway and K+-ATP channel-independent Ca2+-independent pathways of glucose action.10 Other mediators of insulin release include activation of phospholipases and protein kinase C and by stimulation of adenylyl cyclase activity and activation of cell protein kinase A, which potentiates insulin secretion. This latter mechanism may be activated by hormones, such as vasoactive intestinal peptide , PACAP, GLP-1, and GIP. These factors appear to play a significant role in the second phase of glucose mediated insulin secretion, after refilling of secretory granules translocated from reserve pools.10
The Role Of Gpcrs In Circadian Rhythms
New observations have especially intrigued scientists in light of the recently recognized association of sleep disturbances with obesity and risk for type 2 diabetes. Genetic studies have found that a GPCR well known to be involved in sleep rhythms is also important for islet cell function. This GPCR binds to melatonin. Melatonin is best known for its role in sleep and circadian rhythms, but researchers recently learned that individuals who carry a particular mutation in one of the GPCRs that bind to melatonin, melatonin receptor 1B , have higher fasting glucose levels. With that new knowledge in hand, clinical investigators went on to discover that individuals with a mutation in the MTNR1B gene have impaired insulin secretion from their beta cells when glucose levels increase. One manifestation of this is decreased insulin secretion in response to the intake of glucose . Human islets express two different melatonin receptors, 1A and 1B, and the recent recognition of their potential importance to metabolism has increased interest in the role of these GPCRs in alpha and beta cells. While much remains to be learned in this new area of research, it is now clear that circadian rhythms can impact glucose metabolism, in part, through GPCRs expressed in islets.
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How Common Is Insulin Resistance
Since there arent any common tests to check for insulin resistance and there arent any symptoms until it turns into prediabetes or Type 2 diabetes, the best way to measure the prevalence of insulin resistance is through the number of prediabetes cases. More than 84 million adults in the United States have prediabetes. Thats about 1 out of every 3 adults.
When To Contact A Medical Professional
- Chest pain or pressure, shortness of breath, or other signs of angina
- Loss of consciousness
Contact your provider or go to the emergency room if you have symptoms of diabetic ketoacidosis.
Also contact your provider if you have:
- Blood sugar levels that are higher than the goals you and your provider have set
- Numbness, tingling, or pain in your feet or legs
- Problems with your eyesight
- Sores or infections on your feet
- Frequent feelings of depression or anxiety
- Symptoms that your blood sugar is getting too low
- Symptoms that your blood sugar is too high
- Blood sugar readings that are below 70 mg/dL
You can treat early signs of hypoglycemia at home by drinking orange juice, eating sugar or candy, or by taking glucose tablets. If signs of hypoglycemia continue or your blood glucose level stays below 60 mg/dL , go to the emergency room.
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What Is The Difference Between Insulin Resistance And Diabetes
Anyone can develop insulin resistance temporarily or chronically. Over time, chronic insulin resistance can lead to prediabetes and then Type 2 diabetes if its not treated or able to be treated.
Prediabetes happens when your blood glucose levels are higher than normal, but not high enough to be diagnosed as diabetes. Prediabetes usually occurs in people who already have some insulin resistance.
Prediabetes can lead to Type 2 diabetes , the most common type of diabetes. T2D happens when your pancreas doesnt make enough insulin or your body doesnt use insulin well , resulting in high blood glucose levels.
Type 1 diabetes happens when your bodys immune system attacks and destroys the insulin-producing cells in your pancreas for an unknown reason. T1D is an autoimmune and chronic disease, and people with T1D have to inject synthetic insulin to live and be healthy. While T1D is not caused by insulin resistance, people with T1D can experience levels of insulin resistance in which their cells dont respond well to the insulin they inject.
Gestational diabetes is a temporary form of diabetes that can happen during pregnancy. Its caused by insulin resistance thats due to the hormones the placenta makes. Gestational diabetes goes away once you deliver your baby. Approximately 3% to 8% of all people who are pregnant people in the United States are diagnosed with gestational diabetes.
Production Of Hormones To Control Blood Sugar Levels
A small proportion of the pancreas is made up of other types of cells called islets of Langerhans. These cells sit in tiny groups, like small islands, scattered throughout the tissue of the pancreas. The islets of Langerhans contain alpha cells which secrete glucagon and beta cells which secrete insulin.
Insulin and glucagon are hormones that work to regulate the level of sugar in the body to keep it within a healthy range. Unlike the acinar cells, the islets of Langerhans do not have ducts and secrete insulin and glucagon directly into the bloodstream.
Depending on what youve eaten, how much exercise your muscles are doing, and how active your body cells are, the amount of glucose in your bloodstream and cells varies. These 2 hormones have the job of keeping tight control of the amount of glucose in your blood so that it doesnt rise or fall outside of healthy limits.
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Neuroregulation Of Blood Glucose
The autonomic division of the nervous system modulates the release of insulin and glucagon. The sympathetic stimulation that occurs with exercise stimulates glucagon production and this maintains blood-glucose levels that would otherwise fall as muscles use glucose for their energy.
During the periods when the body is at rest, parasympathetic activity stimulates digestion and also the release of insulin to deal with the expected rise in blood glucose.
What Questions Should I Ask My Doctor
If youve been diagnosed with insulin resistance, it may be helpful to ask your healthcare provider the following questions:
- Whats causing my insulin resistance?
- What can I do to increase my insulin sensitivity?
- Whats my risk of developing prediabetes or Type 2 diabetes?
- Is there any medication I can take?
- Should I see a specialist for insulin resistance?
A note from Cleveland Clinic
Insulin resistance is a complex condition that can affect your health in several ways. Since it doesnt have any symptoms until it turns into prediabetes or Type 2 diabetes, the best thing you can do is try to prevent and reverse insulin resistance by maintaining a healthy weight, exercising regularly and eating a healthy diet. Unfortunately, though, not all causes of insulin resistance can be prevented or treated. If you have any questions about your risk of developing insulin resistance or conditions associated with it, talk you your healthcare provider. Theyre there to help you.
Last reviewed by a Cleveland Clinic medical professional on 12/16/2021.
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Regulation Of Insulin Transcription
Insulin biosynthesis is regulated both at transcriptional and translational levels. In a mouse -cell, there are roughly 13,000 insulin granules. They occupy more than 10% of the total cell volume . Each granule contains approximately 200,000 insulin molecules . However, insulin content in -cells is highly dynamic. Insulin accumulates in the presence of nutrients and decreases in response to nutrient deprivation. The ability of -cells to quickly respond to cellular signals is generally due to transcriptional regulation. A number of discrete sequence elements within the promoter region of insulin gene, named A, C, E, Z, and CRE elements determine localization of insulin in -cells and also serve as binding sites for several -cell transcription factors to regulate insulin gene expression . The transcription factor binding sites that are located within a region spanning ~-400 base pairs relative to the TSS are determinants of -cell-specific expression of insulin .
A number of cis- and trans- transcriptional factors are associated with the activation of the insulin enhancer region. In all characterized insulin enhancer sequences the A, C, and E elements are contained in core binding motifs .
Cyclic AMP response element
How Is Insulin Resistance Treated
Since not all factors that contribute to insulin resistance can be treated, such as genetic factors and age, lifestyle modifications are the primary treatment for insulin resistance. Lifestyle modifications include:
- Eating a healthy diet: Your healthcare provider or nutritionist may recommend avoiding eating excessive amounts of carbohydrates and eating less unhealthy fat, sugar, red meats and processed starches. Instead, theyll likely recommend eating a diet of whole foods that includes more vegetables, fruits, whole grains, fish and lean poultry.
- Physical activity: Getting regular amounts of moderate-intensity physical activity helps increase glucose energy usage and improve muscle insulin sensitivity. A single session of moderate-intensity exercise can increase glucose uptake by at least 40%.
- Losing excess weight: Your healthcare provider may recommend trying to lose excess weight to try treating insulin resistance. One study revealed that losing 7% of your excess weight can reduce the onset of Type 2 diabetes by 58%.
Over time, these lifestyle modifications can:
- Increase insulin sensitivity .
- Lower your blood glucose levels.
- Raise HDL cholesterol levels.
You may work with other healthcare providers, such as a nutritionist and endocrinologist, in addition to your regular doctor to come up with an individualized treatment plan that works best for you.
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List Of Foods That Do Not Cause Insulin Release
A list of foods that do not cause insulin release would be nearly identical to a list of foods that do not raise blood sugar, as the two processes are directly linked. Insulin is the hormone that regulates blood sugar levels and allows for the absorption of glucose, which provides energy.
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Functional Measures Of Insulin Resistance
Another approach is to identify insulin resistant patients, based on functional markers of insulin resistance. McLoughlin et al were able to identify insulin resistant individuals from an overweight-obese cohort by looking at plasma triglyceride concentration, ratio of triglyceride to high-density lipoprotein cholesterol concentrations and insulin concentration. Using cut points of 1.47 mmol/L for triglyceride, 1.8 mmol/L for the triglyceride-high-density lipoprotein cholesterol ratio and 109 pmol/L for insulin, they achieved comparable sensitivity and specificity to the Adult Treatment Panel III to diagnose the metabolic syndrome.133
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