In discussing pharmacologic treatments of type 2 diabetes, it is important to remember the two underlying processes of insulin resistance and insulin deficiency leading to hyperglycemia. All secretagogues allow the pancreas I?-cells to secrete insulin in response to a glucose challenge.
Common side effects include hypoglycemia, weight gain, mild gastrointestinal complaints, and rarely skin reactions, photosensitivity, and cholestatic hepatitis.
There are four classes of secretagogues: first and second generation sulfonylureas, meglitinides, and d-Phenylalanine derivatives. Sulfonylureas bind to a sulfonylurea receptors on the I?-cells which stimulate insulin secretion or sensitize the I?-cells to the presence of glucose.
As type 2 diabetes progresses, I?-cells secrete less and less insulin and thus sulfonylureas will not be able to optimize glucose levels by themselves.
D-Phenylalanine derivatives are a faster acting and shorter duration secretagogue than the meglitinides (rapaglinide). Both classes of insulin sensitizers, biguanides and thiazolidinediones, are being researched as possible therapies that delay type 2 diabetes in patients with insulin resistance, glucose intolerance (pre-diabetes), or have high risk for diabetes. Biguanides decrease gluconeogenesis from the liver, increases glucose uptake in muscle tissues, enhances the basal metabolic rate, and may lower food intake because of ita€™s gastrointestinal side effects. Thiazolidinediones have an insulin sensitizing effect on the peroxisome proliferator-activated nuclear receptors in liver cells, adipose tissue, and muscle.
Alpha-glucosidase inhibitors delay disaccharide and complex carbohydrate absorption in the small intestine and allow it to occur instead in the large intestine and colon.
This class is excellent for patients with high 2 hour post meal hyperglycemia, and can be used in people with both insulin resistance and deficiency. Once the decision that medical nutrition therapy and exercise alone are not optimizing a patienta€™s glucose control, the next step is to choose an appropriate oral agent. Most endocrinologists continue to prefer metformin as the optimal first-line agent, particularly in obese patients, and if no contraindications are present. Most patients on monotherapy for diabetes will eventually require a second agent (50% of patients after three years of monotherapy).
The normal pattern of insulin levels throughout the day is illustrated in the chart below.
The pancreas is constantly secreting basal levels of insulin which provides 50% of the bodya€™s requirement.
There are several types of insulin available, and their use is based on the type of insulin therapy and the onset of action required. Basal insulin covers the baseline insulin needs of the body and is usually intermediate acting, extended intermediate acting, or long acting. The onset, peak, and duration of action of these mixtures would reflect a composite of the intermediate and short- or rapid-acting components, with one peak of action. Premixed insulin with NPH and a rapid acting component is more expensive but provides better post meal glucose control. Once the patient is comfortable with a basic insulin regimen and the daily doses is known, most individuals require more aggressive therapy.
Regular insulin can be substituted for patients who snack without bolus coverage or if there is a cost issue for patients. A 200 pound man who is naA?ve to insulin is started on advanced insulin therapy of rapid acting insulin and glargine. He will get an estimated 14 U of glargine at bedtime and 14 U of rapid acting insulin would be distributed over the morning (breakfast), noon (lunch), and evening (dinner) dose.
He will get an estimated 23 U of glargine at bedtime and 23 U of rapid acting insulin would be distributed over the morning (breakfast), noon (lunch), and evening (dinner) dose.
He will get an estimated 34 U of glargine at bedtime and 34 U of rapid acting insulin would be distributed over the morning (breakfast), noon (lunch), and evening (dinner) dose. He will get an estimated 23 U of glargine at bedtime and 46 U of rapid acting insulin would be distributed over the morning (breakfast), noon (lunch), and evening (dinner) dose. Step Five) The 23 U of rapid acting insulin would be distributed over the morning (breakfast), noon (lunch), and evening (dinner) dose. The target glucose level for rapid-acting insulin is achieved when the 2 hour post meal glucose level is within 20 a€“ 40 mg of the pre meal glucose level.A  Patients can also be taught to administer insulin sliding scales in the event of unexpected high glucose levels. Insulin pumps may be useful for some patients as they deliver rapid acting insulin on a continuous basis as a basal dose.
Inhaled insulin is a new dry powder method that will be available soon as it has been approved by the FDA.
Lipodystrophy can happen at sites of injection, with lipohypertrophy occurring more often in men and lipoatrophy occurring more commonly in women. ExpertiseI am an exercise physiologist with a PhD who specializes in diabetes--as such I CANNOT answer general questions about other endocrine problems as I am neither an expert in all areas of endocrinology nor am I a medical doctor. I am using this space to put together my growing understanding of insulin resistance, cell biology of the gut, weight regulation, and nutrition. I am a scientist (PhD Cell Biology) so my discussion here will be very specific regarding the cell biology, genomics, metabolomics, and other matters. The material on this page will seem hodgepodge at first but will become more ordered but more complex over time. There is an as yet to be understood relationship between the participation of the small intestine in the digestive process and the regulation of insulin as well as insulin receptivity of target cells.
We know of this relationship because patients who have had their small intestines by-passed in the weight loss surgery called Roux-en-Y anastomosis have improved insulin utilization but patients who have had the Lap-Band (adjustable gastric band) do not experience the same dynamic.
It is believed that GLP-1 (Glucagon-like peptide 1) is a critical molecule in this metabolic rescue. The following graphic (source) provides some pathway context for the GLP-1 molecule in this setting. Glucagon-like peptide-1 (GLP-1) is derived from the transcription product of the proglucagon gene. GLP-1 secretion by L cells is dependent on the presence of nutrients in the lumen of the small intestine. There are many tissue types in the body and each has its special method of developing over the lifetime of an organism and its own unique metabolism. The plasma level at which glucose appears in the urine is known as the renal threshold for glucose. Even when we resist temptation and stay faithful to our diets, sometimes the extra pounds refuse to go away. There is little doubt that a sedentary lifestyle and eating processed and sugar-filled foods contributes to overweight and obesity.
One under-recognized reason for gaining unwanted pounds is excess levels of the hormone cortisol.
The researchers found that the binge-eating group had higher morning basal cortisol than the non-binge-eating group.
Further testing on the subjects indicated a possible reason why so many people who go on diets fail to achieve optimal weight loss.
The researchers determined that there was a significant relationship between waist circumference, cortisol and peak cortisol stress responsivity after the cold-water test in the binge-eating group even after going on the diet.7 This means that subjects whose cortisol levels were highest had a hard time losing weight, even after dieting. The study authors concluded that, in binge eaters, cortisol appears to be a primary factor in the disorder. On the cancer front, data from the NCI Surveillance, Epidemiology, and End Results (SEER) study estimates that, in 2007, nearly 34,000 new cases of cancer in men (4 percent) and 50,500 in women (7 percent) in the U.S. In another study, 50 stressed people were given 200 mg Relora three times daily for two weeks. Sensoril is standardized to contain the proper amounts of glycowithanolides, withaferin-A and oligosaccarides that research has shown to promote optimal anti-stress activity.
The results showed that WSG induced an anti-anxiety effect comparable to the anti-anxiety drug when the rats were forced to navigate a maze, be involved in social interaction and endure delayed feeding in an unfamiliar environment.
The ability of elevated cortisol to promote insulin resistance may explain why high cortisol is linked to weight gain. The Brown University Medical Student Study further illustrated the relationship between cortisol and insulin. High insulin is the enemy of dieters because insulin, critical for glucose metabolism, storage and maintenance, wasn’t meant to occur in excessive levels. The consumption of excessive amounts of refined carbohydrates and sugar, however, can result in insulin resistance.

Because of cortisol’s ability to elevate insulin levels, when normalizing cortisol levels to achieve weight loss, it is also helpful to stabilize blood sugar. Bitter melon (Momordica charantia) is another substance that has been shown to reduce weight while lowering serum insulin levels.
In a subsequent experiment, rats were placed into four groups that, for seven weeks, consumed one of four diets: a high-fat diet, a high-fat diet plus bitter melon, a low-fat diet or a low-fat diet plus bitter melon. Rats on the high-fat diet plus bitter melon gained less weight and had less visceral fat than those fed the high-fat diet without the bitter melon.
According to the investigators, “This study reveals for the first time that bitter melon reduces adiposity in rats fed a high-fat diet. Galega officinalis (also known as goat’s rue or French lilac) is also reported to support healthy insulin levels and has resulted in weight loss in animal studies and in clinical practice.
In sharp contrast, weight loss in galega-treated, genetically obese mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. 7-Keto® DHEA is a brand name for the compound 3-acetyl-7-oxo-dehydroepiandrosterone, a metabolite of DHEA that, like cortisol, is produced in the adrenal glands.
Similar to DHEA, levels of 7-Keto decline as we age, reaching their peak around age 20, then slowly declining beginning around the age of 30. By boosting the function of thermogenic enzymes in the liver, 7-Keto may also aid in weight loss.
In this double-blind study, all subjects participated in an exercise training program three times per week.
Of the 30 subjects who entered the study, 23 completed the eight-week protocol (seven subjects dropped out for personal reasons unrelated to the study). Additionally, the 7-Keto group experienced a significant increase in levels of the thyroid hormone triiodothyronine (T3) compared to the placebo group. Researchers concluded, “The results of the study suggest that 7-oxo-DHEA [7-Keto DHEA] combined with moderate exercise and a reduced-calorie diet significantly reduces body weight and body fat compared with exercise and a reduced-calorie diet alone. Additionally, cortisol’s role in obesity suggests that supplementing with Relora and Sensoril may positively influence weight loss efforts, especially for those who have had little success with various diets. These two mechanisms are the reasons for checking both fasting and post meal glucose levels. Four of the classes are secretagogues: First and second generation sulfonylureas, meglitinide, and d-Phenylalanine.
Secretagogues are contraindicated in pregnancy, and used with caution in patients with liver disease. Second generation sulfonylureas are more commonly prescribed than first generation, and have less side effects. These drugs are used in patients with polycystic ovarian syndrome which carries a component of insulin resistance. A 500 mg dose started at dinner is recommended and an additional dose can be added to breakfast after a week.
There are several choices for first-line monotherapy as per the American Diabetes Association: metformin, thiazolidinediones, or secretagogues.
First-line therapy with thiazolidinediones is becoming increasingly popular but some cite that there is not enough evidence based information. Using an insulin sensitizing medication along with a secretagogue, or two insulin resistance drugs, are good choices.
Consideration should be given as to whether a patient on triple oral therapy should actually be on insulin. In type 2 diabetes, progressive insulin deficiency makes insulin a useful therapeutic tool. After a meal, the pancreatic I?-cells secretes insulin in response to meals known as bolus levels, which supplies the bodya€™s other 50% requirement. Using the carbohydrate counting method comes in handy to better distribute the bolus amount of rapid acting insulin with each meal. Although it may be more acceptable to administer than injected insulin, it is subject to more variability in patient skill of administration, is less flexible in dosing, may still require injected basal insulin, are contraindicated in patients with lung disease, and its long term effects on the lungs are unknown.
It improves glucose control by mimicking the effects of glucagon-like peptide-1, a natural mammalian incretin hormone secreted during food intake. I may or may not be able to answer your question now but may be able to later, once I have learned it myself. The major source of GLP-1 in the body is the intestinal L cell that secretes GLP-1 as a gut hormone. The secretagogues (agents that cause or stimulate secretion) of this hormone include major nutrients like carbohydrate, protein and lipid. This threshold occurs at a plasma glucose concentration somewhat below the value at which the renal TmGLUCOSE is reached. This can be especially frustrating, since being overweight is far more serious than a cosmetic issue. Researchers have shown that cortisol levels and plasma levels of the appetite-controlling hormone leptin are related to each other in a time-related negative and positive fashion over 24 hours.6 In other words, when cortisol decreases, leptin decreases and when cortisol rises, leptin rises.
In addition, the binge eaters’ cortisol levels were higher after the cold-water stress test. Twenty of the subjects (10 non-binge eaters, 10 binge eaters) were randomized into one of two groups.
Relora®, a proprietary blend of a patented extract from Magnolia officinalis bark and a patent-pending extract from Phellodendron amurense bark, is one of these substances.
Post-trial analysis revealed that 82 percent found Relora effective in controlling stress-induced symptoms, such as depression, anxiety, irritability, emotional ups and downs, concentration difficulties and restlessness. Morning salivary cortisol levels (when cortisol levels are normally highest) dropped 37 percent, while DHEA levels rose 227 percent.
Sensoril is a patented proprietary extract of roots and leaves from Withania somnifera, also known as ashwagandha. One animal study investigated the anxiety-lowering and antidepressant actions of the bioactive Withania somnifera glycowithanolides (WSG) isolated from Withania somnifera roots. In one study of six normal volunteers, researchers administered cortisol infusions into the subjects, which increased the plasma cortisol concentration approximately four-fold to values observed during moderately severe stress. The researchers examined students during a baseline control period as well as during two examination periods. When food is consumed, the digestive process converts carbohydrates into glucose, a simple sugar, which is absorbed into the bloodstream.
The body responds by producing even more insulin, which results in high levels of insulin, glucose and other unabsorbed nutrients circulating in the bloodstream. In one study, oral glucose tolerance was improved in rats fed a high-fat diet supplemented with bitter melon. The addition of bitter melon did not change apparent fat absorption, but bitter melon supplementation to the high-fat diet improved insulin resistance and lowered serum insulin levels. One group of researchers gave mice galega and noted that the herb caused a significant reduction in body weight in both normal and genetically obese animals treated for 28 days.
Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat.
In fact, 7-Keto levels decline nearly 50 percent by age 50.22 7-Keto and DHEA decline more rapidly than cortisol, causing cortisol dominance that can weaken immunity and contribute to weight gain. Thermogenesis is the process in which the body generates heat to help cells metabolize food. When researchers treated 30 healthy, overweight adults (28 women and two men) with 7-Keto DHEA, they uncovered some promising results.
Each exercise session consisted of 50 minutes of cross-training (aerobic and anaerobic exercise) under the supervision of an exercise physiologist.
There were no significant changes in levels of thyroid-stimulating hormone (TSH) or thyroxine (T4) in either group. One of the most effective ways to control cortisol is to first know if you are out of balance. In addition, insulin’s role in weight loss indicates that galega, N-acetylcysteine, quercetin and bitter melon may help dieters shed pounds. Using a combination of these weight-loss efforts, along with healthy diet and a regular exercise program, can ensure plenty of healthy summers for years to come. They also should be used with caution in renal disease (except for repaglinide and nateglinide which dona€™t have renal dosage requirements).

Metformin can decrease or stabilize patient weight, and can reduce cholesterol and triglyceride levels, and may reduce myocardial infarction risk.
It should be withheld prior to any radiology study requiring contrast dye or if going to surgery, and restored once renal function is normal. Two thiazolidinediones, rosiglitazone and pioglitazone, are approved for use in the United States. They are taken within 15 minutes before a meal and are cleared from the body in 2 a€“ 4 hours. Once in the circulation, GLP-1 has a half life of less than 2 minutes, due to rapid degradation by the enzyme dipeptidyl peptidase-4. Insulin functions through at least four mechanisms to promote adipocyte differentiation; two of these mechanisms are common to other regulatory pathways (activation of CREB by cAMP and regulation of GATA factors in the sonic hedgehog (SHH) pathway).
Humoral factors like Wnt ligands, BMP and TGF- transmit their signals through cognate cell membrane receptors expressed by the differentiating cells. Obesity is a risk factor for type 2 diabetes, hypertension and high cholesterol as well as ischemic heart disease,1 cognitive decline,2 stroke3 and hormone-sensitive cancers. Leptin resistance can occur in the body in the same way that insulin resistance can occur, so a rising leptin level could indicate the body needs to produce more of it in order to recognize its effects. One group was put on a six-week program that included cognitive behavioral treatment to help them make better dietary choices. The enzyme 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) regenerates cortisol from cortisone within fat tissue and the liver. In a clinical trial, 49 stressed subjects who suffered from stress-induced overeating were given a two-to-three-times-daily dose of Relora for two weeks. Seventy-eight percent reported increased relaxation, while 74 percent had more restful sleep. Withania somnifera has been shown to reduce the effects of stress,13-14 indicating it may help people who are prone to stress-related eating or whose excess pounds are due to unbalanced cortisol levels. During these timeframes, the researchers noted weight changes in self-proclaimed stress eaters compared to non-stress eaters.
The subjects, whose mean body mass index was roughly 32, were randomly divided into two groups.
In addition, each subject was instructed by a registered dietitian to follow a diet of less than 1,800 calories per day. The 7-Keto group also achieved a significant body-fat reduction compared with the subjects taking the placebo.
Most patients begin with a low dose of sulfonylurea and increase them at 1 a€“ 2 week intervals depending on the self-monitored glucose readings and A1C results. Both nateglinide and rapaglinide can be useful in patients who are found to have optimal fasting glucose levels but high post-prandial glucose levels. A It is indicated for patients with insulin resistance and a good consideration in those with cholesterol issues.
Two I±-glucosidase drugs are approved for use in the United States: acarbose and miglitol.
It is contraindicated in patients with liver disease, inflammatory bowel disease, and pregnancy. In most diabetic patients, multiple daily doses are required to strike the right balance between glycemic control and avoiding hypoglycemia. Ultralente acts somewhat longer than NPH and is therefore known as extended intermediate acting insulin. But this year my Fasting blood sugar level is suddenly gone to 118, I did not do the postprandial test this time because I was confident that my sugar blood levels shall be normal. It is a potent antihyperglycemic hormone, inducing glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion. Activation of -catenin signalling is used by both Wnt-family proteins and androgens to repress adipogenesis.
Transcription factors often govern the final cell lineage decision during MSC differentiation, and their transcriptional activities are modulated through crosstalk with cell-membrane receptor-mediated signals. The figure also illustrates that the TmGLUCOSE is much greater than the normal filtered load of glucose. Insulin downregulates 11HSD1, but overweight people often become insulin resistant, meaning they become gradually more immune to insulin’s effects. Insulin then enters certain cells and triggers events that cause the cells to absorb glucose from the blood.
In normal mice, the weight loss was initially associated with a transient reduction in food intake, but was then maintained even in the presence of increased eating above the control level. One group received 100 mg of 7-Keto DHEA twice daily and the other group received a placebo for eight weeks.
This class allows patients the flexibility to skip a dose if they skip a meal thus preventing hypoglycemia. They do not cause hypoglycemia by themselves, but if hypoglycemia develops in conjunction with sulfonylureas or insulin, the patient may use milk to correct their glucose level.
In patients whom there appears to be a greater degree of pancreatic dysfunction as opposed to insulin resistance, secretagogue use is still appropriate. Studies have found that physicians should probably begin using insulin on patients earlier than they do, and that about 50% of type 2 diabetics require insulin to keep their A1C <7%. Postprandial glucose levels tend to be lower with rapid acting than with short acting insulin.
The recommended dosage is 5 mug to 10 mug twice daily subcutaneously before breakfast and dinner.
I do not have a sweet tooth, there is no history of diabetes in the family trees of either my mother's or my father's side and 5 days a week I have a brisk morning walk for 45 minutes and never had a complain of fatigue or lethargy.
Such glucose-dependent action is particularly attractive because when the plasma glucose concentration is in the normal fasting range, GLP-1 no longer stimulates insulin to cause hypoglycemia. Thus, this mechanism is not a regulator of plasma glucose levels but acts to conserve the body's glucose stores which comprise an important source of energy for a wide variety of metabolic processes.
In the presence of increasing food intake, normal mice receiving galega for seven days also showed significant weight loss compared with the controls.
Recommendations regarding the optimal initial drug approach to this disease are always changing.
It is formulated for delayed absorption over 24 hours with no peak levels, can be administered once a day, and has aA  lower risk of hypoglycemia.
It requires both an increased frequency of insulin administration and self monitored glucose levels.
In randomized, placebo-controlled, 30-week clinical studies, exenatide improved glycemic control and promoted weight loss of up to 2.8 kg. Do I repeat my blood sugar test at a different laboratory, or do I see a physician and take his advice? GLP-1 appears to restore the glucose sensitivity of pancreatic I?-cells , with the mechanism possibly involving the increased expression of GLUT2 and glucokinase.
We have used + and – symbols to denote positive and negative effects on adipogenesis that are not understood mechanistically. Rapid acting insulin is a good choice for those who dona€™t snack throughout the day, while short acting insulin may be better for patients who frequently delay eating after an injection or eat throughout the day.
Glargine can not be mixed with other insulin types, and is usually used in conjunction with bolus insulin. Patient education is critical and they must understand the effects of insulin, carbohydrate intake, insulin injection administration, and exercise. The most common adverse effects were nausea, vomiting, diarrhea, and dose-dependent hypoglycemia.
GLP-1 is also known to inhibit pancreatic I?-cell apoptosis and stimulate the proliferation and differentiation of insulin-secreting I?-cells.

What are normal blood sugar levels for hypoglycemia
Headache symptom of high blood sugar


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