Inflammatory cytokines and the risk of cardiovascular complications in type 2 diabetes,how to manage gestational diabetes without insulin,diabetes tipo 2 y la dieta - Reviews


Michael Jay Katz earned a BA from Harvard University and both an MD and a PhD from Case Western Reserve University.
Fran Laughton is a nurse practitioner who earned an RN from City College of San Francisco, a BSN from California State University, Dominguez Hills, and an MSN from Sonoma State University. Fran Laughton is the co-founder, assistant director, and clinical coordinator for the Registered Nursing program at Mendocino College in Ukiah, California. Course Summary Overview of type 2 diabetes, including underlying physiology, clinical forms, prevalence, causes, and complications.
Distinguish between type 1 and type 2 diabetes and Identify the two major abnormalities of glucose metabolism that underlie type 2 diabetes. Explain how to achieve the treatment goal of glycemic control and how to manage any comorbidities. Type 2 diabetes mellitus is a progressive disease that inevitably worsens over time, even with appropriate management and maintenance of the therapeutic regimen. Type 2 diabetes is characterized by two main defects: insulin resistance, in which many cells in the body become less responsive to insulin, and beta cell deterioration that leads to decreased production of insulin by the pancreas. Type 2 diabetes was once called adult onset diabetes because the disease develops slowly and it typically appears in older adults. The average degree of glycemic control can be followed by measuring the patient’s blood concentration of glycosylated hemoglobin, HbA1c. The current degree of glycemic control can be followed by measuring the daily levels of blood glucose before breakfast and after a meal. Reducing hyperglycemia is the best protection against the long-term complications of type 2 diabetes.
In general, lifestyle changes have the longest-lasting results when they are done through structured, supervised programs that have been tailored to the individual patient. When drugs are necessary, patients are typically begun on metformin, an oral drug that reduces the liver’s overproduction of glucose. Incretin therapy is emerging as a viable option for improving glycemic control and has the advantage of fewer hypoglycemic events and less weight gain when compared to the standard therapies currently used to manage T2DM. In addition to glycemic control, therapy for a patient with type 2 diabetes requires special attention to health issues related to potential complications. Diabetes is a disorder that causes repeated episodes of inappropriately high concentrations of glucose in the bloodstream. The problems underlying type 2 diabetes include a diminished ability to secrete insulin (beta-cell defect) and a decreased ability of cells to respond to insulin (impaired glucose uptake). Acute and significant changes in a person’s blood glucose level can cause life-threatening problems. In general, throughout the time period, the percentage of people with diagnosed diabetes increased among all age groups. A person with diabetes is more likely to be hospitalized than is a person without diabetes. As they carry out their tasks, the body tissues continuously remove glucose from the bloodstream.
As a meal containing carbohydrates is eaten and digested, blood glucose levels rise, and the pancreas secretes insulin (see Role of Insulin, below). 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. 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. These signals are delivered throughout the body by two hormones, insulin and glucagon (Maitra, 2009). Insulin is a peptide hormone that is made in the beta cells of the pancreas and is central to regulating carbohydrate and fat metabolism in the body (Wikipedia, 2013b). In the normal body, insulin functions to remove excess glucose, which otherwise would be toxic, from the blood (Wikipedia, 2013b). Insulin has a range of effects, and they can all be categorized as anabolic, or growth-promoting.
Insulin synthesis and release from beta cells is stimulated by rising concentrations of blood glucose.
Glucagon is a powerful regulator of blood glucose levels, and glucagon injections are used to quickly correct severe hypoglycemia. Incretins are glucagon-like peptides, hormones that are made in cells of the small intestine and secreted into the circulation in response to food. Incretins are deactivated quickly by enzymes in the bloodstream and by enzymes on the surface of endothelial cells. 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. In type 2 diabetes, body cells have a decreased response to insulin known as insulin resistance. Insulin resistance is present in a person many years before the appearance of type 2 diabetes. In addition to insulin resistance, type 2 diabetes is characterized by a progressive decrease in the concentration of insulin in the blood.
Not only do the beta cells release less insulin as type 2 diabetes progresses, they release it more slowly and in a different pattern than that of healthy people (Monnier et al., 2009). The propensity for beta cell dysfunction is inherited, but malfunctioning beta cells are not a clinical problem until many years into the disease.
Together, insulin resistance and decreased insulin secretions lead to hyperglycemia, and hyperglycemia causes most of the health problems in type 2 diabetes. Over time, excess glucose attaches nonspecifically to proteins in a process called glycosylation. 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.
Excess intracellular glucose reduces the effectiveness of the intracellular mechanisms that protect against oxidants and oxidative stress.
Type 2 diabetes strikes genetically predisposed people, and the tendencies to develop insulin resistance and beta cell dysfunction are inherited. After reviewing the genetics of type 2 diabetes, we will briefly examine the activating contributions of three additional health problems: obesity, hyperglycemia, and chronic inflammation. A person’s genome is a strong determinant of the chance of developing type 2 diabetes. Type 2 diabetes is polygenic, meaning that it usually involves the expression of more than one problematic gene. Major risk factors for type 2 diabetes include obesity, physical inactivity, unhealthy diet, hyperglycemia, stress, and chronic inflammation.
Excess body fat causes insulin resistance, and the risk for developing type 2 diabetes increases as the proportion of body fat (BMI) increases. One contribution to the growing number of Americans who have type 2 diabetes is the prevalence of obesity. Physical exercise is a sufficiently powerful counterweight to insulin resistance that regular exercise will improve glycemic control and reduce the risk of developing cardiovascular complications in people with type 2 diabetes.
Any diet that leads to obesity also increases a person’s chances of progressing from prediabetes to diabetes. A high-carbohydrate diet stresses the glucose-lowering capacity of a person with prediabetes and accelerates the development of type 2 diabetes. A high-fat, low-fiber diet, especially one that includes saturated and trans fats, causes dyslipidemias, and these metabolic imbalances worsen insulin resistance and foster the development of type 2 diabetes. The chronic hyperglycemia of diabetes is the direct cause of much of the damage done by the disease. Even in the prediabetes stage, people destined to develop type 2 diabetes have immune systems that are overly active. The symptoms are usually gradual in their onset, and the patient may suffer for a length of time before he thinks it necessary to apply for medical aid. In addition to the classic triad of polyuria, polydipsia, and weight loss, people with longstanding diabetes are weak and often hungry, may have blurred vision, and are prone to infections. Uncontrolled diabetes can present with vomiting, abdominal pain, dehydration, mental status changes, or coma (ADA, 2009b).
The initial baseline workup of a patient with type 2 diabetes requires certain key pieces of information.
The initial physical examination focuses on signs of aggravating health problems as well as developing diabetic complications. The fasting plasma glucose (FPG) is taken at least 8 hours after the patient has had any nourishment. For a broader view, indicating the blood glucose levels of the past few months, the percent of hemoglobin that is glycosylated, the A1C (also known as HbA1c) is measured. The current A1C value is an indication of the average blood concentration of glucose over the past few months. The average blood concentration of glucose over the past few months as indicated by the current A1C value (data from ADA, 2009a).
In 2010 the American Diabetic Association adopted standards recommending the use of the A1C test to diagnose diabetes with a threshold set at 6.5%.
The A1C has several advantages over the FPG and OGTT, including greater convenience since a fast is not required, greater analytic stability, and fewer day-to-day adjustments as glycemic values fluctuate in response to stress and illness.
The advantages of A1C testing should be balanced against some of the known variables to accurate A1C values, namely the presence of anemias or other hemoglobinopathies.
Point of Care testing with the A1C test is not considered adequate for diagnostic purposes unless it conforms to the Diabetes Control and Complications Trial reference assay (NIDDK, 2008). Type 2 diabetes comes on gradually, and it takes many years to reach a level at which its effects are clinically apparent. An impaired fasting glucose, which is a fasting plasma glucose level between normal and diabetes (see table). An impaired glucose tolerance, which is an oral glucose-tolerance test result between normal and diabetes (see table).
Step two in treating prediabetes is anti-diabetic drug therapy, especially for patients at high risk for developing diabetes complications.
There is strong evidence from randomized multi-center interventional trials that metformin or acarbose reduce the progression of prediabetes to diabetes. Patients with prediabetes should also be treated to reach the same lipid and blood pressure goals as patients with diabetes. Heart disease is the most common cause of death for people with type 2 diabetes, and the reduction of cardiovascular risk is a top priority for people with diabetes.
A number of interrelated disorders significantly increase anyone’s chance of developing cardiovascular diseases, with the resulting possibility of myocardial infarction or stroke.
To reduce the cardiovascular risk, each of these disorders should be treated when it occurs in a patient. While a person can have any one of these problems, each of these cardiometabolic disorders fosters the others. A number of researchers have pointed out that focusing on those particular cardiometabolic risk factors called metabolic syndrome does not appear to improve medical care (Kahn, 2006; ICCMR, 2009), and the rationale behind the creation of a metabolic syndrome has been questioned. Treatment of the metabolic syndrome involves the separate treatment of each of its components.
In addition, a patient with diabetes should see an ophthalmologist for an annual dilated eye exam.
Patients with diabetes do best when they understand their disease and when they know how to manage their lives to keep their blood sugar levels as normal as possible.
In the following sections, we review the major goals and strategies used in managing type 2 diabetes. One way to monitor a patient’s glycemic control is to chart fasting (FPG) and postprandial (PPG) blood glucose levels. Patients need to be trained in the proper use of a home glucose monitor, and they should have time to practice in front of a diabetes nurse.
Currently, there is no consensus on how frequently people with type 2 diabetes should check their blood glucose levels if they are not taking insulin (ADA, 2009a). Lowering A1C to below or around 6.5% has been shown to reduce microvascular and neuropathic complications of type 1 and type 2 diabetes. One of the first steps in helping an overweight person regain better control of their blood glucose levels is to encourage them to lose weight.
There are no magic weight loss diets, and it is always necessary to reduce people’s daily calories for them to lose weight. The patient’s diet is an important component of the plan to keep blood glucose levels under control. Although numerous studies have attempted to identify the optimal mix of macronutrients for meal plans of people with diabetes, it is unlikely that one such combination of macronutrients exists. Most important is the reduction in saturated fatty acids, trans fatty acids, and cholesterol.
When eating a varied diet, patients need to estimate the carbohydrate content of many different meals. The current recommendations are 14 g of dietary fiber per day for every 1,000 calories of food; this is 25 g of dietary fiber daily for women and 38 g for men (Amer. Antioxidant supplements (eg, vitamin C, vitamin E, or carotene) are not currently recommended.
Regular exercise helps patients with type 2 diabetes to control their blood glucose levels and reduces their risk of developing cardiovascular disease.
More exercise leads to better health, and patients who already exercise at a moderate-intensity level can be encouraged to increase their intensity level. In addition to poor glycemic control, certain other conditions require diabetic patients to check with their doctor before beginning an exercise program.
To have a significant effect, regular activity must become a continuing part of a patient’s life.
Over time, type 2 diabetes worsens, and the degree and the frequency of hyperglycemia increase into a range that threatens tissue damage, resulting in eye, kidney, nerve, and artery problems. Insulin, metformin, sulfonylureas and others have long been considered the mainstay of treatment for patients with T2DM. Combination therapies are more effective than single-drug therapies, and when metformin is not sufficient to keep A1C levels under 6.5% another medication is added.
Thiazolidinediones, or TZDs, as they are commonly known, are a class of medication introduced in the early 1990s to treat T2DM.
The first agent in this class, troglitazone (Rezulin) was taken off the market in the late 1990s due to an increased incidence of drug-induced hepatitis. Currently there are restrictions and warnings on the two drugs in the class that are still available with regard to their ability to cause or worsen CHF, as well as the association of Actos with bladder cancer. Two types of incretin-based therapy are now in use: incretin mimetics (glucagon-like peptide GLP-1), which bind with specific receptors, and incretin enhancers (dipeptidyl peptidase-4, or DPP-4), which inhibit the enzyme that degrades incretin hormones.
Used early in therapy, GLP-1s and DPP-4s preserve beta-cell function and secretion, which has the potential to slow the progression of the disease. Clinical trials and post marketing reports have identified additional safety risks that are under active investigation for the incretin-based therapies. Renal safety is an additional consideration with the GLP-1 agents and the DPP-4 agent saxagliptin. The amylin analog pramlintide (Symlin) has many of the same incretin actions of the GLP-1 agents, except that it does not stimulate insulin secretion; it acts by slowing gastric emptying, thus suppressing glucagon release by the liver. In March of 2013, another new agent, camagliflozin (Invokana) was approved for use is patients with T2DM. Invokana was approved by the FDA based on nine studies involving more than 10,000 patients. The most common side effects seen with this agent are yeast infections and urinary tract infections arising from increased amounts of sugar in the urine. Because this drug is new, the FDA is requiring the manufacturer to conduct five follow-up studies to ensure the drug’s safety. Invokana is only recommended for patients with T2DM and should not be used in those patients who have severe renal impairment or end-stage renal disease, or for those receiving dialysis. NBD peptide administration did not affect the metabolic severity of diabetes but resulted in renal protection, as evidenced by dose-dependent decreases in albuminuria, renal lesions (mesangial expansion, leucocyte infiltration and fibrosis), intranuclear NF-I?B activity and proinflammatory and pro-fibrotic gene expression. Peptide-based inhibition of IKK complex formation attenuates NF-I?B activation, suppresses inflammation and retards the progression of renal and vascular injury in diabetic mice, thus providing a feasible approach against diabetes inflammatory complications. IntroductionDiabetes mellitus is a disease of metabolic dysregulation, characterised by hyperglycaemia and the development of diabetes-specific pathology. Clinical and experimental evidence implicates NF-I?B activation and regulated genes in the early phases, progression and final complications of diabetes and, as such, its inhibition offers therapeutic intervention opportunities [11a€“17]. Primary mouse mesangial cells (MC), vascular smooth muscle cells (VSMC) and a proximal tubuloepithelial cell line (MCT) were cultured in medium containing 10% FCS (Life Technologies, Rockville, MD, USA) [21a€“24].
Fluorescence microscopy in VSMC (Fig.A 1b) and MCT (not shown) revealed a time-dependent delivery of cell-permeable rhodamine-conjugated NBD peptide that was homogeneously distributed in the cytoplasm. We further analysed the expression of T helper (Th) representative genes in spleen, the major source of cytokines involved in the initiation of systemic inflammation.
DiscussionNephropathy and atherosclerosis are common vascular complications in type 1 and type 2 diabetes. AO, CR and IL contributed to study design, data acquisition and analysis, and drafted the manuscript.
He has taught anatomy and physical diagnosis in the medical school of Case Western Reserve University for thirty years. Most important, cardiovascular and microvascular complications may be prevented or delayed when glycemic levels are optimized. For many individuals, up to 50% of beta cell function is lost by the time the diagnosis is made.
Type 1 diabetes is an autoimmune disease in which the patient’s body makes antibodies to its own pancreatic beta cells. Even before the disease shows clinical signs and symptoms, mildly elevated blood glucose levels can be detected in blood tests. Over the years, the individual’s prediabetes worsens, especially if the person is overweight and inactive.
Ninety to ninety-five percent of all present cases of diabetes are type 2; however, the age at which the condition is being diagnosed continues to decline. This test represents a more stable average blood glucose over the preceding 120-day period. Home glucose monitors, which require ever-smaller amounts of blood to produce a reliable readout, have improved this aspect of management; however, these values fluctuate to a considerable degree during the course of a day.
Daily blood glucose levels should be measured by the patients themselves as part of their multifaceted self-care program.
The effective therapies for minimizing hyperglycemia and increasing glycemic control in patients with type 2 diabetes include therapeutic lifestyle changes (weight loss, exercise, improved diet) and medications. If metformin does not reduce a patient’s hyperglycemia sufficiently, other oral drugs are added. Diabetes patients need routine blood pressure, blood lipid, kidney, and eye examinations, and aggressive treatment for problems when they appear. As countries become wealthier, their populations become more sedentary and eat a richer diet, both of which foster the development of type 2 diabetes. This chronic hyperglycemia gradually produces tissue damage, notably to eyes, kidneys, nerves, heart, and blood vessels.
Type 1 diabetes usually results from autoimmune destruction of the beta cells in the pancreas. The stress of illness often significantly increases blood glucose levels in the hospitalized patient. People with diabetes are 2 to 4 times more likely to die of heart disease than people without diabetes. People with diabetes are 2 to 4 times more likely to have a stroke than people without diabetes.
In the United States, the majority of nontraumatic leg or foot amputations is in people with diabetes. In a normal person, a meal of carbohydrates replenishes the circulating blood glucose during a window that begins about 10 minutes after eating and continues until 2 hours after eating.
Glucose from the bloodstream enters liver cells, stimulating the action of several enzymes that convert the glucose to chains of glycogen as long as both insulin and glucose remain plentiful. Intestinal hormones and elevated blood levels of two amino acids, leucine and arginine, also cause beta cells to release insulin (Maitra, 2009).
Glucagon causes the liver to convert stored glycogen into glucose, which is released into the bloodstream. People with type 2 diabetes have excess glucagon secretion, which is a contributor to the chronic hyperglycemia of type 2 diabetes.
Exenatide (Byetta), an injectable anti-diabetes drug, is categorized as a glucagon-like peptide-1 (GLP-1) and directly mimics the glucose-lowering effects of natural incretins upon oral ingestion of carbohydrates.
Therefore, the glucose-lowering effects of incretins last only a few minutes (Drucker & Nauck, 2006).
After a meal, the muscles in a person with type 2 diabetes take up too little glucose, leaving blood glucose levels elevated for extended periods (Basu et al., 2009).
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. People inherit a propensity for developing insulin resistance, and a number of other health problems worsen the condition.
At first, the beta cells manage to manufacture and release sufficient insulin to compensate for the higher demands caused by insulin resistance.
The beta cells’ production capacity is eroded more quickly when the cells are bathed in excess glucose and excess insulin.
For example, HbA1c, the chemical measured to monitor average glycemic levels, is glycosylated hemoglobin. For example, if a dizygotic (fraternal) twin develops type 2 diabetes, the chances are about 25% that the other twin will also develop the disease. More than twenty variant genes have been documented as potential contributors to the development of type 2 diabetes, and the problematic genes are found on a number of chromosomes.
These health problems are neither absolute nor independent causes of the disease—that is, not all people with these problems develop type 2 diabetes.
The risk is higher when the excess fat has accumulated inside the abdominal cavity, as opposed to under the skin, and excess intra-abdominal fat is a feature of more than 4 out of 5 patients with type 2 diabetes. Excess fat, especially visceral fat, leads to higher blood levels of fatty acids, and fatty acids reduce glucose uptake (cause insulin resistance) in skeletal muscle.
In the south and central United States, 25% or more of the population is clinically obese (CDC, 2010).
In part, this results from the tendency of sedentary people to accumulate triglycerides in their muscle cells.
Chronic hyperglycemia also worsens the underlying causes of type 2 diabetes and accelerates the loss of glycemic control. Together, insulin resistance, hyperglycemia, and hyperinsulinemia induce a low-level persistent inflammatory reaction. In addition to blood tests, the initial examination of a patient suspected of having diabetes includes a history and physical examination that look for signs of diabetic tissue damage. The first symptoms that attract attention are failure of strength, and emaciation, along with great thirst and an increased amount and frequent passage of urine. In the United States today, however, type 2 diabetes is usually identified before its symptoms have become extreme. The A1C test is thought to reflect average glycemia over several months’ time and is strongly predictive of diabetic complications at higher levels. For conditions with abnormal red blood cell turnover such as pregnancy, recent blood loss, and transfusion, the diagnosis of diabetes must still use blood glucose tests exclusively. Before this time, however, blood tests will already show that the patient s body cannot keep blood glucose concentrations as tightly controlled as a healthy person can.
In October 2010 the Food and Drug Administration (FDA) recommended against further use of this drug, as it is associated with unnecessary cardiovascular risks to patients. Among other side effects, the manufacturer reports increased incidence of metabolic acidosis and hypoglycemia in diabetic patients who take medication to control hyperglycemia, making it a less than ideal agent for this population. High-risk patients include those with metabolic syndrome, current cardiovascular disease, progressively worsening hyperglycemia, nonalcoholic fatty liver disease (NASH), a history of gestational diabetes, or polycystic ovary syndrome. Food and Drug Administration for the prevention of diabetes in adults, nor are there any approved pharmacologic options for use in children or adolescents. While both agents are less effective than intensive lifestyle interventions, they do have relatively good safety profiles. For example, insulin resistance can lead to dyslipidemia and hypertension, hypertension increases the likelihood of developing diabetes, and central obesity can lead to insulin resistance. Actually, there have been many names and at least five overlapping definitions (Rosenzweig et al., 2008).
Second, the treatment for metabolic syndrome is the same as the treatment for whichever of its components are present. All patients should have a medical home that is responsible for monitoring the patient’s health, but many of the specific healthcare tasks are carried out by licensed nurses, certified diabetic educators, dieticians, and other specialists.


A licensed nurse with special training and education should teach each patient how to check daily blood glucose levels, how to take medications, and how to care for injuries and wounds. A critical part of caring for people with diabetes is explaining the overall treatment plan and teaching the patients how to care for themselves (diabetes self-management education) (ADA, 2009a).
The patient’s current degree of glucose control is ascertained, the presence and state of any diabetes complications are assessed, and the existing aggravating conditions, such as obesity or physical inactivity, are noted. Each item on the list is assigned a goal, and a specific strategy for reaching the goal is written down. The doctor and the patient will both have the overall plan in mind and will be able to monitor its progress and share its successes.
Poor glycemic control leads to frequent or continuous hyperglycemia, which is the underlying cause of diabetic health problems. These measurements are taken at home, and the patient or a family member must learn to use a home glucose meter and must stick to a pre-assigned schedule of test times. Regularly scheduled monitoring will provide a record of daily glucose fluctuations for their physician. Patients taking diabetes medications, especially insulin, should also be taught how to adjust their medications, diet, and activity in response to hypoglycemia and hyperglycemia.
Excess weight is a direct cause of insulin resistance, and as the excess weight increases, the glycemic control decreases. Formal weight loss programs that include low-calorie diets, behavior modification, and regular exercise have been shown to produce sufficient weight loss to improve the glycemic control of overweight patients with type 2 diabetes.
In the long run, low-carbohydrate diets (<130 g carbohydrates) seem to be about as effective and as safe as low-fat diets, but without special effort, either variety of diet typically produces only modest weight loss (ADA, 2009a). An organized approach to a patient’s overall diet and eating habits is called medical nutrition therapy. The best mix of carbohydrate, protein, and fat appears to vary depending on individual circumstances (ADA, 2009a). Nonetheless, there are some general principles that can be used as a starting point for patients with type 2 diabetes (ADA, 2009a). For this, carbohydrate counting or carbohydrate exchange rulesare two methods that are widely used and not difficult to learn. The minimum recommendation is 30 minutes of moderate-intensity physical activity on each of 3 days every week.
Some people with type 2 diabetes who are taking insulin or insulin secretagogues will become hypoglycemic with exercise.
Patients with severe peripheral neuropathy can unknowingly damage their feet during exercise that is hard on their lower limbs. For example, people who have been sedentary should begin their exercise program at low intensity and should increase the amount and time of their physical activities gradually (Marwick et al., 2009). Patients stick to exercise goals more consistently when the activities are undertaken in a structured, supervised program—for example, when they attend regular classes or when they keep a record and report regularly to a supervisor.
Initially, a patient’s metabolic compensatory mechanisms may be able to avoid significant periods of hyperglycemia, and, in the prediabetes stage, there may be only mild hyperglycemia. When therapeutic lifestyle changes become insufficient to maintain good glycemic control, it is time to add non-insulin medications. More recently they have been joined by a number of newer medications with varying potencies, mechanisms of action, and adverse effect profiles. It has similar or superior effects to second-generation sulfonylureas and to the more expensive TZDs and meglitinides. Clinicians are advised to carefully consider the risks and benefits of TZDs as well as combination products containing them. They both promote weight loss (or are weight neutral) by slowing gastric emptying and increasing satiety. The three GLP-1 agents are injectables with varying dosing schedules that range from QD and BID to weekly(QW) dosing. Pancreatitis has been reported with each of the six agents, but a clear association has not yet been established, as people with T2DM already have a three-fold higher incidence compared to normoglycemic control. In general, saxagliptin has safety considerations with all the more serious adverse-effect categories: pancreatitis, cardiovascular effects, hypersensitivity, renal and hepatic events, and increased risk for bone fracture compared to other agents in this group. These investigations should identify safety concerns with greater reliability than post marketing reports. In theory, this process also carries at least the potential for promoting earlier satiety, with the result that fewer calories are consumed at a meal leading to subsequent weight loss. Invokana is taken as an oral agent, once daily, and acts by blocking kidneys from re-absorbing sugar into the bloodstream.
Specifically, the FDA will track rates of cardiac problems, cancer, pancreatitis, liver abnormalities, severe hypersensitivity reactions, photosensitivity, and other problems in order to determine safety. Kidneys and aorta were analysed for morphology, leucocyte infiltrate, collagen, NF-I?B activity and gene expression.
Furthermore, peptide treatment limited atheroma plaque formation in diabetic mice by decreasing the content of lipids, leucocytes and cytokines and increasing plaque stability markers.
Complications affecting the macrovasculature and microvasculature are the major causes of morbidity and mortality among diabetic patients [1].
Ex vivo confocal microscopy studies were performed after a single dose of rhodamine-labelled peptide. Further co-localisation experiments demonstrated that NBD inhibits the nuclear translocation of the p65 subunit in MCT and VSMC after short-term HG incubation (Fig.A 1c). Fluorescence experiments revealed efficient accumulation of rhodamine-peptide in mouse tissues (Fig.A 3a). Picrosirius red staining (Fig.A 3b, d) also demonstrated reduced renal fibrosis in NBD-treated mice.
Diabetic kidneys displayed an intense nuclear staining widely distributed in glomeruli and tubulointerstitium, whereas a significant decrease in the number of NF-I?B+ cells was observed in NBD-treated groups (Fig.A 7aa€“c). However, the pathogenesis of renal and vascular injury in diabetic patients has not been completely clarified, and treatments are limited and unsatisfactory [4, 5].
This finding is in agreement with that of a recently published report showing that NBD improved vascular dysfunction (in terms of myogenic tone and endothelium-dependent relaxation) in coronary and mesenteric resistance arteries from a mouse model of type 2 diabetes [45].
BM, JB and JE contributed to conception and design, data analysis, and reviewed the manuscript for intellectual content. The Diabetes Control and Complications Trial (DCCT) demonstrated as long ago as 1993 that microvascular complications could be significantly reduced when glycemic goals are maintained. An additional 3% to 5% may be lost in each subsequent year (UK Prospective Diabetes Study Group, 1998).
People with type 1 diabetes cannot make sufficient insulin to survive, and the disease is sometimes called insulin-dependent diabetes.
People with long-standing type 2 diabetes can have cardiovascular damage, kidney destruction, retinal damage, peripheral nerve damage, foot problems, poor wound healing, and an increased risk of developing Alzheimer’s disease. Drugs are chosen and adjusted according to the severity of the particular person’s diabetes and the existence of other health problems. Because type 2 diabetes usually includes increasing failure of the pancreatic beta cells, many patients eventually need to take supplemental insulin. More than 3% of the world population has been diagnosed with diabetes, with the highest concentrations in developed countries.
Americans living in poverty are more likely to have diabetes than middle-class and affluent Americans. These individuals are often managed using a sliding-scale insulin regimen during hospitalization. Outside of that approximately two-hour period, the liver replenishes the circulating blood glucose by dipping into its store of glycogen. The liver both converts glycogen back to glucose when it is needed for energy and regulates the amount of glucose circulating between meals.
When it reaches the liver, glucagon stimulates gluconeogenesis, the breakdown of glycogen, and the export of glucose into the circulation.
They also slow the rate of absorption of nutrients into the bloodstream by reducing gastric emptying and they may directly reduce food intake. When a person with type 2 diabetes is fasting, the liver secretes too much glucose, and it continues to secrete glucose after the blood level becomes too high (Basu et al., 2009).
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. Eventually, however, the defective beta cells decrease their insulin production and can no longer meet the increased demand. The hyperglycemia and hyperinsulinemia caused by the over-stressed beta cells hastens their own failure.
Glycosylated proteins trigger inflammatory reactions, which injure the lining of blood vessels.
It appears that, to develop type 2 diabetes, other health problems must intervene to activate or worsen the latent insulin resistance and beta cell dysfunction (Maitra, 2009).
The disease risk doubles if the twins are monozygotic (identical): if a monozygotic twin develops type 2 diabetes, the chances are about 50% that the other twin will also develop the disease (Maitra, 2009). Nonetheless, they are major risk factors because they help to initiate or to worsen type 2 diabetes in people with the predisposition for it. Moreover, in obese individuals, adipose tissue releases less adiponectin, a hormone that reduces insulin resistance. By mechanisms that are not completely understood, skeletal muscle and adipose tissue that become overloaded with glucose are less able to take up more glucose, thus hyperglycemia contributes to insulin resistance (Buse et al., 2008). Their blood has persistent, subclinical elevations of molecules of inflammation, such as C-reactive protein and interleukin-6. The following is a brief review of the special features of an initial examination for type 2 diabetes.
From the normal quantity of from 2 to 3 pints in the 24 hours it may be increased to 10, 20, or 30 pints, or even more. The A1C value increases steadily with increasing average blood concentration of glucose (see graph). In contrast, a person with an FPG and an OGTT in the prediabetes range has about a 65% of developing diabetes in 6 years (Garber et al., 2008). Therefore, people tend to have more than one of these disorders at a time (Buse et al., 2008). If other cardiometabolic risk factors, such as smoking, physical inactivity, clinical depression, or chronic mental stress are present, they need to be addressed, too. Diabetes self-management education is often the job of a nurse who is also a certified diabetes educator. Regular monitoring also makes patients aware of how various events and meals affect their particular blood sugar levels.
Variability, such as swings between hyperglycemia and hypoglycemia, are smoothed out, so A1C values do not give an indication of the volatility of a patient’s glucose levels. When the excess fat is visceral (inside the abdomen as opposed to directly under the skin), the diabetogenic effect is worse (Maitra, 2009).
In medical nutrition therapy, registered dieticians specializing in diabetes work with patients to plan both meal content and eating schedules.
Therefore, intense exercise should be limited to patients with satisfactory glycemic control whose bodies can cope with jumps in their blood glucose levels. Patients with satisfactory glycemic control are least likely to develop severe hypoglycemia.
When patients no longer have the ability to keep their blood glucose levels appropriately low, adequate glycemic control can usually be maintained with a planned diet, weight reduction, and increased physical exercise.
The following box lists the medicines commonly prescribed to reduce the hyperglycemia of type 2 diabetes.
The goal of all medication regimes used to manage diabetes is to maintain glucose levels as near normal as possible while minimizing the danger of hypoglycemia or other adverse effects. Healthcare providers (HCPs) choose by balancing cost, drug side effects, and the individual patient’s tolerance for the medicine.
As a group, these drugs have had an interesting history characterized by initial high hopes alternating with the agents receiving strong warnings or being removed from the market altogether.
In September 2010, rosiglitazone was withdrawn from the market in Germany and France and placed under restrictions in the United States due to these cardiovascular effects. Similar to the other GLP-1 agonists, Symlin is administered as a subcutaneous injection prior to meals.
This action results is less sugar being absorbed from food, and consequently, less being stored in the liver as glycogen.
In January 2013, the FDA noted that the drug may carry some increased heart risks during the first 30 days of use, suggesting the need for increased surveillance and careful patient selection.
We therefore investigated the functional consequences of targeting the IKK-dependent NF-I?B pathway in the progression of diabetes-associated nephropathy and atherosclerosis.
This nephroprotective and anti-atherosclerotic effect was accompanied by a decline in systemic T helper 1 cytokines.
Diabetic nephropathy, which largely contributes to end-stage renal disease, is an important risk factor for macrovascular disease, while atherosclerosis is the main reason for impaired life expectancy in diabetic patients [2, 3]. This work investigates whether IKK-targeted NF-I?B inhibition improves diabetic complications. At the study endpoint, 16A h-fasted mice were anaesthetised, saline-perfused and killed, and organs were collected.
A non-significant effect of NBD peptide was observed in the renal samples from non-diabetic groups (Fig.A 3ba€“d).
Concurrently, NBD treatment also resulted in a dose-dependent decrease in the gene and protein expression of chemokines and cytokines in the aorta of diabetic mice (Fig.A 6aa€“c). Furthermore, NBD administration dose-dependently decreased NF-I?B activation in atherosclerotic lesions (Fig.A 7a, d). Analysis of NF-I?B+ cells in glomeruli (b), tubulointerstitium (c) and atherosclerotic lesions (d). This is consistent with the hypothesis that key pathogenic mechanisms and intracellular pathways leading to progression of diabetes complications are not modified by the current therapies [11, 20]. Importantly, we observed that NF-I?B inhibition altered plaque composition and inflammation in mouse atherosclerotic lesions without affecting serum lipid levels. Blanco-Colio (Nephrology Department, IIS-Fundacion Jimenez Diaz, Madrid, Spain) for material and intellectual support, and M.
CGG obtained funding, conceived and designed the study, analysed the data and wrote the manuscript. With the variable levels of circulating glucose come organ damage: nephropathy, neuropathies, retinopathies, and other circulatory defects. Given the rapid increase in the number of people with this condition, and the increasingly younger age when the disease is diagnosed, healthcare providers need to be conversant in detection, management, education, and preventive strategies in order to decrease the overall burden to society. Type 1 diabetes has also been called juvenile diabetes because it typically appears in children and young adults.
The consequences are serious: in the United States, diabetes is the main cause of kidney failure, adult-onset blindness, and nontraumatic amputations of legs and feet. Initially, people with type 2 diabetes can live without additional insulin; after a time, however, the disease worsens and many people with type 2 diabetes eventually need insulin supplements.
Overall, the risk for death among people with diabetes is about twice that of people without diabetes of similar age (NIDDK, 2008).
Glycogen is a polysaccharide, made and stored primarily in the cells of the liver, that serves as a form of energy storage.
After a meal has been digested and blood glucose levels begin to fall, insulin secretion drops and glycogen synthesis stops. Duplication of this process is the goal of therapy when glucose levels are managed externally. In these ways, the effects of glucagon are catabolic, the opposite of insulin’s anabolic effects (Drucker, 2008). 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.
In this way, high levels of blood lipids decrease the effectiveness of insulin; in other words, high blood lipids increase insulin resistance.
By way of excess triglycerides, physical inactivity and obesity increase insulin resistance (Monnier et al., 2009). In type 2 diabetes, the continual loss of functioning beta cells shows up as a progressive deterioration in glycemic control.
In addition, glycosylated proteins stick together in basement membranes of capillaries, thickening the endothelial coats and disrupting their normal function. Instead, the expressions of a variety of combinations of problematic genes will each give a form of type 2 diabetes.
Excess adipose tissue also secretes additional pro-inflammatory molecules (cytokines), which increase insulin resistance. Chronic stress thus leads to hyperglycemia, which, in turn, increases insulin resistance, and this fosters type 2 diabetes in predisposed people. Among the effects of these molecules (the pro-inflammatory cytokines) is an elevation in the level of adrenocorticotropic hormone (ACTH), which is the direct stimulant of cortisol secretion. It is usually of pale colour, and of thicker consistence than normal urine, possesses a decidedly sweet taste, and is of high specific gravity. By identifying patients with prediabetes, it is possible to intervene and improve their future health and quality of life. Therefore, it has been argued that the attention given to the metabolic syndrome is a distraction from the need to thoroughly treat all of a person s cardiometabolic risk factors.
If the patient is having psychological or mood problems, a mental health professional should be involved (ADA 2009a).
Type 2 diabetes is a life-long illness, and patients need a life-long plan for diabetes management. The goals are to minimize hyperglycemic episodes and to fit the proper meals into each particular patient’s lifestyle.
Those patients who tend to get hypoglycemic easily can prepare for exercise by lowering their insulin dose or by increasing their carbohydrate intake before exercising.
It also poses a smaller risk of adverse events than second-generation sulfonylureas and TZDs.
HCPs and patients can feel comfortable using older medications such as metformin and second-generation sulfonylureas, as monotherapy or in combination, before newer diabetes medications such as TZDs or meglitinides, especially when cost is a factor (Bolen et al., 2007). In February 2011, the FDA issued an advisory that no new patients be started on this agent, and consideration be given regarding patient preference that they switched to another drug in the class, pioglitazone (Actos).
Use of these agents as monotherapy has a low association with hypoglycemia and there is no recommendation for increased self-monitoring of blood glucose (SMBG); however, when used in combination with a secretagogue or insulin, more frequent monitoring of blood glucose is recommended (ADA, 2012).
Serious adverse effects have been noted and are under investigation, as will be discussed below.
Also similar to the GLP-1 agents, it is associated with significant nausea, which may limit the ability to administer the agent at therapeutic doses.
Hyperglycaemia, hyperlipidaemia and chronic inflammation are involved in the clinically well-recognised complications of diabetes. NF-I?B DNA-binding activity was assessed by an ELISA-based assay (Active Motif, Carlsbad, CA, USA).
Peptide administration had no significant effect on hyperglycaemia, body weight and serum lipid profile in diabetic mice (TableA 1). In fact, the decrease in atheroma size correlated with reduced numbers of macrophages and T cells within the lesions of diabetic mice and reduced aortic expression of pro-inflammatory factors (CCL2, CCL5 and TNFI±) involved in migration and activation of vascular cells. Gonzalez (IIS-Fundacion Jimenez Diaz, Madrid, Spain) for technical assistance with the confocal microscope. Diabetes hospitalizations are largely due to the other major health problems caused or worsened by diabetes. Glycogen provides an energy reserve that can be quickly mobilized to meet a sudden need for glucose (Wikipedia, 2013a).
When it is needed for energy, glycogen is broken down and once again converted to glucose (Wikipedia, 2013a). Thus, glucagon and insulin are part of a feedback system that keeps blood glucose levels stable (Wikipedia, 2013). An additional incretin-like agent, dipeptidyl peptidase-4 (DPP-4), is available in the form of several orally administered products. In type 2 diabetes, beta cells seemingly exhaust their capacity to adapt to the long-term demands of peripheral insulin resistance (Maitra, 2009).
The increased insulin resistance from all these causes leads to hyperinsulinemia, and this hyperinsulinemia further weakens dysfunctional beta cells (Maitra, 2009).
Inflammation tends to increase the level of blood glucose while decreasing the amount of glucose cleared from the blood; that is, inflammation causes hyperglycemia and insulin resistance. It is important that people taking insulin have more immediate feedback about their blood glucose concentration. Appropriately planned eating has been shown to reduce the A1C levels of patients with type 2 diabetes by 2% to 3% in 6 months.
Therefore, noninsulin drug treatment of type 2 diabetes typically begins with metformin (Bolen et al., 2007).
In spring of 2011 pioglitazone had a warning issued due to an increased association with bladder cancer when used over 12 months.
In fact, released inflammatory cytokines and chemokines contribute to atherosclerotic plaque formation, while growth factors and adhesion molecules promote inflammatory cell recruitment into the renal microvasculature, predisposing patients to diabetic nephropathy development [4, 5].The nuclear factor-I?B (NF-I?B) intracellular pathway controls numerous biological processes and its activation has been linked to many pathological conditions including inflammatory diseases [6, 7].
Gene expression after long-term co-incubation of peptide with HG and LPS was analysed by real-time quantitative PCR (Applied Biosystems, Foster City, CA, USA). Throughout the study, neither overt toxicity or lethality, nor hepatic or splenic damage were observed in NBD-treated groups (not shown). NF-I?B gene polymorphisms influence the susceptibility to type 1 and 2 diabetes and affect microvascular and atherosclerotic complications in patients [13, 28, 29]. Hyperglycemia can no longer be matched by excess insulin secretion, and the person develops clinical diabetes (Maitra, 2009). Therefore, daily FPG and PPG monitoring is crucial for those with insulin-dependent diabetes.
Real-time PCR values normalised by 18S are expressed as percentage vs stimulus (a) and fold increase vs basal (arbitrarily set to 1; ba€“e). Serum transaminase activities were also similar across the groups (TableA 1), indicating preserved liver function. Hyperglycaemia, dyslipidaemia, oxidative stress and inflammation can also lead to the occurrence of diabetes complications by activating canonical NF-I?B-driven genes [15]. Considering that most acute clinical events of atherosclerosis, such as myocardial infarction and stroke, are caused by the rupture of an unstable (leucocyte- and lipid-rich, collagen-poor) plaque [46], efficient strategies to modulate harmful NF-I?B-mediated cell responses by directly targeting IKK could be of benefit in slowing lesion progression.Besides a local anti-inflammatory effect on mouse kidney and aorta, we also detected an indirect action of NBD on systemic inflammation, as evidenced by reduced splenic expression of pro-inflammatory Th1 cytokines, but not anti-inflammatory Th2 genes.
Pramlintide (Symlin) carries a black box warning for severe hypoglycemia 3 hours post injection.
Sustained inhibition (up to 24A h exposure) was also observed in HG-stimulated VSMC (Fig.A 2e). Remarkably, NBD treatment dose-dependently improved renal function in diabetic mice, as evidenced by significant reductions of serum creatinine, urine albumin-to-creatinine and kidney-to-body weight ratios (TableA 1). Studies in animal models with either total or cell-specific inactivation of NF-I?B family members (e.g. It is well recognised that NF-I?B transcriptional activity directly controls the main cytokine drivers of the Th1 response [7, 47]. Thus, NF-I?B subunits (predominantly the p65a€“p50 heterodimer) are released and translocated to the nucleus where they regulate inflammatory gene transcription [6, 7].
Remarkably, NBD peptide did not influence cell viability, but it was able to inhibit, in a dose-dependent manner, the proliferation of MC induced by long-term exposure to HG (Fig.A 2f).
Furthermore, elevated levels of Th1 cytokines correlate with proteinuria [48] and the risk of cardiovascular complications [49] in patients with type 2 diabetes. Nevertheless, in a carefully selected population, the lowering of the HgA1c by up to 1% and the associated weight loss may result in significant improvement in overall management of diabetes.
The IKK complex is formed by two catalytic subunits (IKKI± and IKKI?) and the regulatory subunit (NF-I?B essential modulator [NEMO]) [8].
Representative immunoblots and summary of normalised densitometric quantification are shown. In all these experiments, no significant effects were observed with mutant peptide (FigsA 1, 2).
Moreover, anti-inflammatory compounds exhibit an ameliorating effect on diabetic symptoms and long-term complications by directly inhibiting IKK activity [33, 34], although limitations due to cellular toxicity and immunosuppression have prompted a search for alternative strategies [19]. Consistent with this, our findings indicate that regulation of the systemic Th1-mediated immunoinflammatory response may account, at least in part, for the in vivo protective effect of NBD in diabetic mice.In conclusion, our results demonstrate that NBD peptide potently inhibits NF-I?B-mediated inflammatory responses in diabetic mice, thereby preventing the progression of diabetes-associated nephropathy and atherosclerosis. Results expressed as relative increases over basal (arbitrarily set to 1) are meansa€‰A±a€‰SEM of 3a€“5 independent experiments each performed in duplicate assays. Given the pivotal role of NF-I?B activation in diabetes development, we suggest selective inhibition of the IKK-dependent canonical NF-I?B pathway as a feasible approach against diabetes inflammatory complications.
Gene expression was analysed by real-time quantitative PCR and normalised to housekeeping 18S. Serum lipids and transaminases were measured by automated methods, blood HbA1c and urine albumin by ELISA (Gentaur, Kampenhout, Belgium; Cell Trend, Luckenwalde, Germany) and creatinine by enzymatic assay (Abcam, Cambridge, UK).



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