What does diabetes cause a resistance to?
Beta cell
Type 2 diabetes mellitus, also known as non insulin dependent diabetes and as chronic hyperglycemia, is caused primarily by genetics and the development of obesity. The beta cells can still secrete insulin but the body has developed a resistance and its response to insulin has declined. It is believed to be due to the decline of specific receptors on the surface of the liver, adipose, and muscle cells which lose their ability to respond to insulin that circulates in the blood. In an effort to secrete enough insulin to overcome the increasing insulin resistance, the beta cells increase their function, size and number. Increased insulin secretion leads to hyperinsulinemia, but blood glucose levels remain within their normal range due to the decreased efficacy of insulin signaling. However, the beta cells can become overworked and exhausted from being overstimulated, leading to a 50% reduction in function along with a 40% decrease in beta-cell volume. At this point, not enough insulin can be produced and secreted to keep blood glucose levels within their normal range, causing overt type 2 diabetes.
Disposition index
Disposition index (DI) is the product of insulin sensitivity times the amount of insulin secreted in response to blood glucose levels. Insulin resistant individuals can maintain normal responses to blood glucose due to the fact that higher levels of insulin are secreted as long as the beta cells of the pancreas are able to increase their output of insulin to compensate for the insulin resistance. Loss of function of the beta cells, reducing their capacity to compensate for insulin resistance, results in a lower disposition index.
Pancreas
Diabetes mellitus type 1 is a chronic autoimmune disorder in which the immune system attacks the insulin-secreting cells of the pancreas. Insulin is needed to keep blood sugar levels within optimal ranges, and its lack can lead to high blood sugar. As an untreated chronic condition, diabetic neuropathy can result. Type 1 diabetes can develop at any age but is most often diagnosed before adulthood. For people living with type 1 diabetes, insulin injections are critical for survival.
Insulin resistance
The most common type of insulin resistance is associated with overweight and obesity in a condition known as the metabolic syndrome. Insulin resistance often progresses to full Type 2 diabetes mellitus (T2DM) or latent autoimmune diabetes of adults. This often is seen when hyperglycemia develops after a meal, when pancreatic β-cells are unable to produce sufficient insulin to maintain normal blood sugar levels (euglycemia) in the face of insulin resistance. The inability of the β-cells to produce sufficient insulin in a condition of hyperglycemia is what characterizes the transition from insulin resistance to T2DM.
Complications of diabetes mellitus
Furthermore, reduced sympathoadrenal responses can cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure (HAAF) in diabetes posits that recent incidents of hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. In many cases (but not all), short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in affected patients, although this is easier in theory than in clinical experience.
Diabetes mellitus
"Brittle" diabetes, also known as unstable diabetes or labile diabetes, is a term that was traditionally used to describe the dramatic and recurrent swings in glucose levels, often occurring for no apparent reason in insulin-dependent diabetes. This term, however, has no biologic basis and should not be used. Still, type 1 diabetes can be accompanied by irregular and unpredictable high blood sugar levels, frequently with ketosis, and sometimes with serious low blood sugar levels. Other complications include an impaired counterregulatory response to low blood sugar, infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (e.g., Addison's disease). These phenomena are believed to occur no more frequently than in 1% to 2% of persons with type 1 diabetes.
Diabetes management
Because many patients with diabetes have two or more comorbidities, they often require multiple medications. The prevalence of medication nonadherence is high among patients with chronic conditions, such as diabetes, and nonadherence is associated with public health issues and higher health care costs. One reason for nonadherence is the cost of medications. Being able to detect cost-related nonadherence is important for health care professionals, because this can lead to strategies to assist patients with problems paying for their medications. Some of these strategies are use of generic drugs or therapeutic alternatives, substituting a prescription drug with an over-the-counter medication, and pill-splitting. Interventions to improve adherence can achieve reductions in diabetes morbidity and mortality, as well as significant cost savings to the health care system. Smartphone apps have been found to improve self-management and health outcomes in people with diabetes through functions such as specific reminder alarms, while working with mental health professionals has also been found to help people with diabetes develop the skills to manage their medications and challenges of self-management effectively.
Subclinical diabetes
Subclinical diabetes is a stage of hyperinsulinemia due to insulin resistance in normoglycemic individuals and, therefore, not diagnosed for hyperglycemic states characteristic of diabetes mellitus. It anticipates the prediabetes and diabetes stages characterized by hyperglycemia among other glucocentric biomarkers. Insulin resistance can be diagnosed by measures of plasma insulin, both fasting or during a glucose tolerance test.
Pituitary pars intermedia dysfunction
The trigger to insulin resistance is not fully understood. Genetics is likely to have some impact on the risk of postprandial hyperinsulinemia. Obesity, pregnancy, PPID, and inflammatory states may contribute to tissue insulin resistance. PPID is thought to result in increased insulin secretion due to higher levels of CLIP produced by melanotrophs, and to cause insulin resistance secondary to hyperadrenocorticism.
Insulin resistance
The "Diabetes Prevention Program" (DPP) showed that exercise and diet were nearly twice as effective as metformin at reducing the risk of progressing to type 2 diabetes. However, the participants in the DPP trial regained about 40% of the weight that they had lost at the end of 2.8 years, resulting in a similar incidence of diabetes development in both the lifestyle intervention and the control arms of the trial. One 2009 study found that carbohydrate deficit after exercise, but not energy deficit, contributed to insulin sensitivity increase.
Diabetes mellitus
The primary complications of diabetes due to damage in small blood vessels include damage to the eyes, kidneys, and nerves. Damage to the eyes, known as diabetic retinopathy, is caused by damage to the blood vessels in the retina of the eye, and can result in gradual vision loss and eventual blindness. Diabetes also increases the risk of having glaucoma, cataracts, and other eye problems. It is recommended that diabetics visit an eye doctor once a year. Damage to the kidneys, known as diabetic nephropathy, can lead to tissue scarring, urine protein loss, and eventually chronic kidney disease, sometimes requiring dialysis or kidney transplantation. Damage to the nerves of the body, known as diabetic neuropathy, is the most common complication of diabetes. The symptoms can include numbness, tingling, pain, and altered pain sensation, which can lead to damage to the skin. Diabetes-related foot problems (such as diabetic foot ulcers) may occur, and can be difficult to treat, occasionally requiring amputation. Additionally, proximal diabetic neuropathy causes painful muscle atrophy and weakness.
Downregulation and upregulation
This process is illustrated by the insulin receptor sites on target cells in a person with type 2 diabetes. Due to the elevated levels of blood glucose in an overweight individual, the β-cells (islets of Langerhans) in the pancreas must release more insulin than normal to meet the demand and return the blood to homeostatic levels. The near-constant increase in blood insulin levels results from an effort to match the increase in blood glucose, which will cause receptor sites on the liver cells to downregulate and decrease the number of receptors for insulin, increasing the subject’s resistance by decreasing sensitivity to this hormone. There is also a hepatic decrease in sensitivity to insulin. This can be seen in the continuing gluconeogenesis in the liver even when blood glucose levels are elevated. This is the more common process of insulin resistance, which leads to adult-onset diabetes.
Neonatal diabetes mellitus
Moreover, half of TNDM patients that contain chromosome 6q24-related TNDM experiencing re-occurrence of diabetes during their childhood or young adulthood. The onset of insulin resistance and increased insulin requirements are associated with puberty and pregnancy initiating the relapse of diabetes. In the event of remission, individuals do not show symptoms or impairment Beta-cell function in the fasting state. Insulin secretory response to intravenous glucose loading might be abnormal in those destined to have a relapse of diabetes. TNDM caused by 6q24 genomic defects are always associated with IGUR. Other contributing factors are umbilical hernia and enlarged tongue, which are present in 9 and 30% of patients with chromosome 6q24 related TNDM.
Insulin receptor
The main activity of activation of the insulin receptor is inducing glucose uptake. For this reason "insulin insensitivity", or a decrease in insulin receptor signaling, leads to diabetes mellitus type 2 – the cells are unable to take up glucose, and the result is hyperglycemia (an increase in circulating glucose), and all the sequelae that result from diabetes.
Pancreas
Diabetes mellitus type 2 is the most common form of diabetes. The causes for high blood sugar in this form of diabetes usually are a combination of insulin resistance and impaired insulin secretion, with both genetic and environmental factors playing an important role in the development of the disease. The management of type 2 diabetes relies on a series of changes in diet and physical activity with the purpose of reducing blood sugar levels to normal ranges and increasing insulin sensitivity. Biguanides such as metformin are also used as part of the treatment along with insulin therapy.
Diabetic nephropathy
Diabetes causes a number of changes to the body's metabolism and blood circulation, which likely combine to produce excess reactive oxygen species (chemically reactive molecules containing oxygen). These changes damage the kidney's glomeruli (networks of tiny blood vessels), which leads to the hallmark feature of albumin in the urine (called albuminuria). As diabetic nephropathy progresses, a structure in the glomeruli known as the glomerular filtration barrier (GFB) is increasingly damaged. This barrier is composed of three layers including the fenestrated endothelium, the glomerular basement membrane, and the epithelial podocytes. The GFB is responsible for the highly selective filtration of blood entering the kidney's glomeruli and normally only allows the passage of water, small molecules, and very small proteins (albumin does not pass through the intact GFB). Damage to the glomerular basement membrane allows proteins in the blood to leak through, leading to proteinuria. Deposition of abnormally large amounts of mesangial matrix causes periodic-acid schiff positive nodules called Kimmelstiel–Wilson nodules.
Diabetes in Aboriginal Australians
Diabetes, in particular, non-insulin dependent diabetes, is prevalent in the Aboriginal and Torres Strait Islander populations of Australia. As many as 1 in 20 Australians are said to suffer from diabetes, and of this amount, Aboriginals are three times as likely to succumb to this disease, in comparison to non-Aboriginals. In contrast with type 1 diabetes, which is a predisposed autoimmune condition, type 2 diabetes or insulin resistant diabetes, is a preventable disease, heavily influenced by a multitude of socioeconomic factors. Sufferers of the disease are consequently more susceptible to chronic health issues, including heart disease and renal failure. Conclusively, this has contributed to the 17 year life expectancy gap between Aboriginals and non-Aboriginals and in turn, has led to disparity and inequity of health between Aboriginals and non-Aboriginals.
FOXO1
Because FOXO1 provides a link between transcription and metabolic control by insulin, it is also a potential target for genetic control of type 2 diabetes. In the insulin-resistant murine model, there is increased hepatic glucose production due to a loss in insulin sensitivity; the rates of hepatic gluconeogenesis and glycogenolysis are increased when compared to normal mice; this is presumably due to un-regulated FOXO1. When the same experiment was repeated with haploinsufficient FOXO1, insulin sensitivity was partially restored, and hepatic glucose production subsequently decreased. Similarly, in mice fed with a high fat diet (HFD), there is increased insulin resistance in skeletal and liver cells. However, when haploinsufficient FOXO1 mice were treated with the same HFD, there was a notable decrease in insulin resistance in both skeletal and liver cells. This effect was significantly augmented by the simultaneous administration of rosiglitazone, which is a commonly prescribed anti-diabetic drug. These results create an opportunity for a novel gene therapy based approach to alleviating insulin desensitization in type 2 diabetes.
Vitamin A receptor
STRA6 has also been associated with facilitating insulin resistance. This is because STRA6 signaling results in activation of transcription factor STAT5 target genes. One of these target genes is a suppressor of cytokine signaling 3 (SOCS3) which is a strong inhibitor of insulin signaling. As a result, STRA6 signaling suppresses the response to insulin by inhibiting the phosphorylation of the insulin receptor, IR, by an influx of insulin. In other words, increased levels of the RBP in obese animals (which will increase STRA6 activity) can facilitate insulin resistance. Due to this close relationship between STRA6 and insulin resistance, it has been demonstrated that single nucleotide polymorphisms in STRA6 are associated with Type 2 Diabetes.
Metabolic syndrome
It is common for there to be a development of visceral fat, after which the adipocytes (fat cells) of the visceral fat increase plasma levels of TNF-α and alter levels of a number of other substances (e.g., adiponectin, resistin, and PAI-1). TNF-α has been shown not only to cause the production of inflammatory cytokines, but also possibly to trigger cell signaling by interaction with a TNF-α receptor that may lead to insulin resistance. An experiment with rats fed a diet with 33% sucrose has been proposed as a model for the development of metabolic syndrome. The sucrose first elevated blood levels of triglycerides, which induced visceral fat and ultimately resulted in insulin resistance. The progression from visceral fat to increased TNF-α to insulin resistance has some parallels to human development of metabolic syndrome. The increase in adipose tissue also increases the number of immune cells present within, which play a role in inflammation. Chronic inflammation contributes to an increased risk of hypertension, atherosclerosis and diabetes.
MicroRNA
Another class of miRNAs that regulate insulin resistance, obesity, and diabetes, is the let-7 family. Let-7 accumulates in human tissues during the course of aging. When let-7 was ectopically overexpressed to mimic accelerated aging, mice became insulin-resistant, and thus more prone to high fat diet-induced obesity and diabetes. In contrast when let-7 was inhibited by injections of let-7-specific antagomirs, mice become more insulin-sensitive and remarkably resistant to high fat diet-induced obesity and diabetes. Not only could let-7 inhibition prevent obesity and diabetes, it could also reverse and cure the condition. These experimental findings suggest that let-7 inhibition could represent a new therapy for obesity and type 2 diabetes.
Tuberculosis
Primary resistance occurs when a person becomes infected with a resistant strain of TB. A person with fully susceptible MTB may develop secondary (acquired) resistance during therapy because of inadequate treatment, not taking the prescribed regimen appropriately (lack of compliance), or using low-quality medication. Drug-resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also resistant to three or more of the six classes of second-line drugs. Totally drug-resistant TB is resistant to all currently used drugs. It was first observed in 2003 in Italy, but not widely reported until 2012, and has also been found in Iran and India. Bedaquiline is tentatively supported for use in multiple drug-resistant TB.
Pain
Insensitivity to pain may also result from abnormalities in the nervous system. This is usually the result of acquired damage to the nerves, such as spinal cord injury, diabetes mellitus (diabetic neuropathy), or leprosy in countries where that disease is prevalent. These individuals are at risk of tissue damage and infection due to undiscovered injuries. People with diabetes-related nerve damage, for instance, sustain poorly-healing foot ulcers as a result of decreased sensation.
Insulin resistance
Fast food meals combined with drinks containing sugar typically possess several characteristics, all of which have independently been linked to IR: they are sugar rich, palatable, and cheap, increasing risk of overeating and leptin resistance; simultaneously, they are high in dietary fat and fructose, and low in omega-3 and fiber; and they usually have high glycemic indices. Overconsumption of cheap sugar rich meals and beverages have been proposed as a fundamental factor behind the metabolic syndrome epidemic and all its constituents.
Genetic causes of diabetes mellitus type 2
Genetic cause and mechanism of type 2 diabetes is largely unknown. However, single nucleotide polymorphism (SNP) is one of many mechanisms that leads to increased risk for type 2 diabetes. To locate genes and loci that are responsible for the risk of type 2 diabetes, genome wide association studies (GWAS) was utilized to compare the genomes of diabetic patient group and the non-diabetic control group. The diabetic patients’ genome sequences differ from the controls' genome in specific loci along and around numerous genes, and these differences in the nucleotide sequences alter phenotypic traits that exhibit increased susceptibility to the diabetes. GWAS has revealed 65 different loci (where single nucleotide sequences differ from the patient and control group's genomes), and genes associated with type 2 diabetes, including "TCF7L2", "PPARG", "FTO", "KCNJ11","NOTCH2", "WFS1", "IGF2BP2", "SLC30A8", "JAZF1", "HHEX, DGKB, CDKN2A, CDKN2B, KCNQ1, HNF1A, HNF1B MC4R, GIPR, HNF4A, MTNR1B, PARG6, ZBED3, SLC30A8, CDKAL1, GLIS3, GCKR," among others."KCNJ11" (potassium inwardly rectifying channel, subfamily J, member 11), encodes the islet ATP-sensitive potassium channel Kir6.2, and "TCF7L2" (transcription factor 7–like 2) regulates proglucagon gene expression and thus the production of glucagon-like peptide-1. In addition, there is also a mutation to the Islet Amyloid Polypeptide gene that results in an earlier onset, more severe, form of diabetes. However, this is not a comprehensive list of genes that affects the proneness to the diabetes.
Anti-diabetic medication
Insulin sensitizers address the core problem in type 2 diabetes – insulin resistance.
Insulin resistance
Variation in the NAT2 gene is associated with insulin resistance by affecting insulin sensitivity. Specifically, it is believed that the rs1208 loci near the NAT2 gene plays a role in insulin resistance. One study showed that when the expression of the NAT1 gene, the mouse equivalent of NAT2, is reduced there was a decrease in insulin stimulated glucose uptake and therefore decreases insulin sensitivity.  Further research has shown that loci near the GCKR and IGFI genes are linked to insulin resistance. Several other loci have also been determined to be associated with insulin insensitivity. These loci however, are estimated to only account for 25-44% of the genetic component of insulin resistance.
Glutamate receptor
Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, to be specific the malfunctioning NMDA glutamate receptors during early stages of the disease.
Diabetes mellitus and deafness
Diabetes mellitus and deafness (DAD) or maternally inherited diabetes and deafness (MIDD) or Mitochondrial Diabetes is a subtype of diabetes which is caused from a point mutation at position 3243 in human mitochondrial DNA, which consists of a circular genome. This affects the gene encoding tRNALeu. Because mitochondrial DNA is contributed to the embryo by the oocyte and not by spermatozoa, this disease is inherited from maternal family members only. As indicated by the name, MIDD is characterized by diabetes and sensorineural hearing loss.
Sleep deprivation
It has been suggested that people experiencing short-term sleep restrictions process glucose more slowly than individuals receiving a full 8 hours of sleep, increasing the likelihood of developing type 2 diabetes. In 2005, a study of over 1400 participants showed that participants who habitually slept few hours were more likely to have associations with type 2 diabetes. However, because this study was merely correlational, the direction of cause and effect between little sleep and diabetes is uncertain. The authors point to an earlier study which showed that experimental rather than habitual restriction of sleep resulted in impaired glucose tolerance (IGT). Sleep deprivation can cause insulin resistance in the body, triggering the onset of early diabetes.
Insulin resistance
Insulin resistance is often associated with abnormalities in lipids particularly high blood triglycerides and low high density lipoprotein.
Insulin resistance
One of insulin's functions is to regulate delivery of glucose into cells to provide them with energy. Insulin resistant cells cannot take in glucose, amino acids and fatty acids. Thus, glucose, fatty acids and amino acids 'leak' out of the cells. A decrease in insulin/glucagon ratio inhibits glycolysis which in turn decreases energy production. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types such as fat and muscle cells require insulin to absorb glucose. When these cells fail to respond adequately to circulating insulin, blood glucose levels rise. The liver helps regulate glucose levels by reducing its secretion of glucose in the presence of insulin. This normal reduction in the liver's glucose production may not occur in people with insulin resistance.
Beta blocker
A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. Clinical guidelines in Great Britain, but not in the United States, call for avoiding diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes.
Insulin resistance
Inflammation by itself also seems to be implicated in causing insulin resistance. Mice without JNK1-signaling do not develop insulin resistance under dietary conditions that normally produce it. Recent study have found out the specific role of the MLK family of protein in the activation of JNK during obesity and insulin resistance.
Sweetened beverage
The hallmarks of type II diabetes (T2DM) pathogenesis are insulin resistance and impaired insulin secretion. In the earlier stages of disease development, cells throughout the body become resistant to the effects of insulin. Therefore, insulin is unable to cause cells to take up glucose (among other impairments) and glucose builds up in the blood. As a result, insulin secretion is ramped up, to try to compensate for this lack of response. For a while this may work, but eventually, the body's ability to secrete insulin from the pancreatic beta cells gets burnt out. In later stages of T2DM, patient cells are both resistant to insulin effects and the pancreas has lost its ability to produce adequate insulin in response to glucose. Type II diabetes is a progressive disease which eventually can lead to patients becoming dependent on exogenous insulin to lower their blood glucose levels.
Sleep and metabolism
Insulin-Resistant Metabolism
Diabetes mellitus type 2
Other potentially important mechanisms associated with type 2 diabetes and insulin resistance include: increased breakdown of lipids within fat cells, resistance to and lack of incretin, high glucagon levels in the blood, increased retention of salt and water by the kidneys, and inappropriate regulation of metabolism by the central nervous system. However, not all people with insulin resistance develop diabetes, since an impairment of insulin secretion by pancreatic beta cells is also required.
Diabetic ketoacidosis
DKA most frequently occurs in those who know they have diabetes, but it may also be the first presentation in someone who had not previously been known to be diabetic. There is often a particular underlying problem that has led to the DKA episode; this may be intercurrent illness (pneumonia, influenza, gastroenteritis, a urinary tract infection), pregnancy, inadequate insulin administration (e.g. defective insulin pen device), myocardial infarction (heart attack), stroke or the use of cocaine. Young people with recurrent episodes of DKA may have an underlying eating disorder, or may be using insufficient insulin for fear that it will cause weight gain.
Hugh McDevitt
Dr. McDevitt is most well known for his discovery of immune response genes and the first definitive physical map of the Major Histocompatibility Complex (MHC). Specifically, his work focused on how the histocompatibility molecules regulate the immune response and their role in the development and function of the immune system. McDevitt has won awards "for his landmark discovery and identification of genes that control immune responsiveness, and his subsequent elucidation of mechanisms of antigen recognition and induction of the immune response." His research focuses on identifying and understanding how certain cells and specific sequence polymorphisms in a class II MHC molecule initiate diabetes and how T cells can prevent and suppress the transfer of diabetes. Along with Dr. Qing Li, they discovered that interferon-alpha, and immune signal, can trigger the onset of type-1 diabetes. "A normal process - programmed cell death - causes a normal response," McDevitt said. "But it does this in such a way that, in a small subset of the population, it starts them on the road to type-1 diabetes." He is considered an expert in the field of major histocompatibility class II molecules. Currently, his laboratory is working on identifying peptide fragments of proteins which lead to the inflammation and destruction of islet beta cells. 
He has also achieved worldwide acclaim for his contributions to arthritis research.
Microangiopathy
One cause of microangiopathy is long-term diabetes mellitus. In this case, high blood glucose levels cause the endothelial cells lining the blood vessels to take in more glucose than normal (these cells do not depend on insulin). They then form more glycoproteins on their surface than normal, and also cause the basement membrane in the vessel wall to grow abnormally thicker and weaker. Therefore they bleed, leak protein, and slow the flow of blood through the body. As a result, some organs and tissues do not get enough blood (carrying oxygen & nutrients) and are damaged, for example, the retina (diabetic retinopathy) or kidney (diabetic nephropathy). Nerves and neurons, if not sufficiently supplied with blood, are also damaged, which leads to loss of function (diabetic neuropathy, especially peripheral neuropathy).
Tumstatin
Diabetic nephropathy as a result of diabetes mellitus is a result of persistent high blood sugar, and is characterized by a lessened globular filtration rate. The mechanism behind diabetic nephropathy is similar to that of angiogenesis, and for this reason, tumstatin may have implications in treating the disease. It was found that VEGF is one of the mediators of glomerular hypertrophy, which causes nephropathy. Since tumstatin inhibits the binding of VEGF, it inhibits diabetic nephropathy as well as resulting in decreased glomerular hypertrophy and hyperfiltration. 
These findings suggest that tumstatin might be used as a treatment for diabetes by regulating the angiogenesis pathways.
Insulin resistance
This hypothesis raises the point that if there is a genetic component to insulin resistance and Type 2 Diabetes, these phenotypes should be selected against. Yet, there has been an increase in mean insulin resistance in both the normoglycemic population as well as the diabetic population.
Proinsulin
Increased levels of proinsulin in the circulatory system relative to mature insulin concentrations can indicate impending insulin resistance and the development of type 2 diabetes. Additional problems with proinsulin that can lead to diabetes include mutations in the number of cysteines present, which could affect correct folding. If the mutation causes only a mild change it could simply stress the endoplasmic reticulum’s ability to properly fold the protein. This stress, after a while, would lead to a decrease in the number of β-cells producing mature insulin, and would then lead to diabetes mellitus.
Diabetes mellitus type 2
Type 2 diabetes is due to insufficient insulin production from beta cells in the setting of insulin resistance. Insulin resistance, which is the inability of cells to respond adequately to normal levels of insulin, occurs primarily within the muscles, liver, and fat tissue. In the liver, insulin normally suppresses glucose release. However, in the setting of insulin resistance, the liver inappropriately releases glucose into the blood. The proportion of insulin resistance versus beta cell dysfunction differs among individuals, with some having primarily insulin resistance and only a minor defect in insulin secretion and others with slight insulin resistance and primarily a lack of insulin secretion.
CD20
A link between the immune system's B cells and diabetes mellitus has been determined. In cases of obesity, the presence of fatty tissues surrounding the body's major organ systems results in cell necrosis and insulin desensitivity along the boundary between them. Eventually, the contents of fat cells that would otherwise have been digested by insulin are shed into the bloodstream. An inflammation response that mobilizes both T and B cells results in the creation of antibodies against these cells, causing them to become less responsive to insulin by an as-yet unknown mechanism and promoting hypertension, hypertriglyceridemia, and arteriosclerosis, hallmarks of the metabolic syndrome. Obese mice administered anti-B cell CD-20 antibodies, however, did not become less responsive to insulin and as a result did not develop diabetes mellitus or the metabolic syndrome, the posited mechanism being that anti-CD20 antibodies rendered the T cell antibodies dysfunctional and therefore powerless to cause insulin desensitivity by a B cell antibody-modulated autoimmune response. The protection afforded by anti-CD-20 lasted approximately forty days—the time it takes the body to replenish its supply of B cells—after which repetition was necessary to restore it. Hence, it has been argued that diabetes mellitus be reclassified as an autoimmune disease rather than a purely metabolic one and focus treatment for it on immune system modulation.
Biomarkers of diabetes
In T2DM patients Nesfatin-1 is elevated and this could possibly be as a result of a resistance. Thus, Nesfatin-1 acts as a potent Anorexigenic factor (anti-obesity) that improves insulin resistance and opposes weight gain.
Anti-diabetic medication
Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in type 1, which must be injected.
HNF1A
In humans, mutations in HNF1A cause diabetes that responds to low dose sulfonylurea agents. The identification of extreme sulfonylurea sensitivity in patients with diabetes mellitus owing to heterozygous mutations in HNF1A presents a clear example of the relevance of HNF1A in diabetes patients and how pharmacogenetics can contribute in patient care. For example, patients with maturity onset diabetes of the young owing to mutations in HNF1A (which accounts for ~3% of all diabetes mellitus cases diagnosed under the age of 30 years) are extremely sensitive to sulfonylurea treatment and can successfully transition off insulin treatment. Likewise, patients with diabetes caused by mutations in the HNF1A gene have been described as sensitive to the hypoglycemic effects of sulphonylureas. The cause of hyperglycemia appears to alter the response to hypoglycemic drugs. Accordingly, HNF-1α-induced diabetes has marked sulphonylurea sensitivity. This pharmacogenetic effect is consistent with models of HNF-1α deficiency, and the genetic basis of hyperglycemia may have implications for patient management.
Drug resistance
Drug, toxin, or chemical resistance is a consequence of evolution and is a response to pressures imposed on any living organism. Individual organisms vary in their sensitivity to the drug used and some with greater fitness may be capable of surviving drug treatment. Drug-resistant traits are accordingly inherited by subsequent offspring, resulting in a population that is more drug-resistant. Unless the drug used makes sexual reproduction or cell-division or horizontal gene transfer impossible in the entire target population, resistance to the drug will inevitably follow. This can be seen in cancerous tumors where some cells may develop resistance to the drugs used in chemotherapy. Chemotherapy causes fibroblasts near tumors to produce large amounts of the protein WNT16B. This protein stimulates the growth of cancer cells which are drug-resistant. MicroRNAs have also been shown to affect acquired drug resistance in cancer cells and this can be used for therapeutic purposes. Malaria in 2012 has become a resurgent threat in South East Asia and sub-Saharan Africa, and drug-resistant strains of "Plasmodium falciparum" are posing massive problems for health authorities. Leprosy has shown an increasing resistance to dapsone.
Diabetic retinopathy
Diabetic retinopathy affects up to 80 percent of those who have had diabetes for 20 years or more. At least 90% of new cases could be reduced with proper treatment and monitoring of the eyes. The longer a person has diabetes, the higher his or her chances of developing diabetic retinopathy. Each year in the United States, diabetic retinopathy accounts for 12% of all new cases of blindness. It is also the leading cause of blindness in people aged 20 to 64.
Diabetes mellitus type 1
The cause of type 1 diabetes is unknown. A number of explanatory theories have been put forward, and the cause may be one or more of the following: genetic susceptibility, a diabetogenic trigger, and exposure to an antigen.
Insulin resistance
Various disease states make body tissues more resistant to the actions of insulin. Examples include infection (mediated by the cytokine TNFα) and acidosis. Recent research is investigating the roles of adipokines (the cytokines produced by adipose tissue) in insulin resistance. TNF-α has been found in increased amounts in obese patients. Due to its effects on adipocytes it is possible that excessive TNF-α is one of several factors that leads to insulin resistance. TNF-α can inhibit lipogenesis, promote lipolysis, disrupt insulin signaling, and reduce the expression of GLUT4. Animal studies have tested the theory by reducing the expression of TNF-α and its receptor in obese animals.Beneficial results were found in some studies, supporting the idea that TNF-α plays a role in insulin resistance.
Genetic causes of diabetes mellitus type 2
While obesity is an independent risk factor for type 2 diabetes that may be linked to lifestyle, obesity is also a trait that may be strongly inherited. Other research also shows that type 2 diabetes can cause obesity as an effect of the changes in metabolism and other deranged cell behavior attendant on insulin resistance.
Diabetes in cats
Diabetes mellitus is a chronic disease in cats, whereby either insufficient insulin response or insulin resistance lead to persistently high blood glucose concentrations. Diabetes could affect up to 1 in 230 cats, and may be becoming increasingly common. Diabetes mellitus is less common in cats than in dogs. 80-95% of diabetic cats experience something similar to type-2 diabetes, but are generally severely insulin-dependent by the time symptoms are diagnosed. The condition is treatable, and treated properly, the cat can experience a normal life expectancy. In type-2 cats, prompt effective treatment may lead to diabetic remission, in which the cat no longer needs injected insulin. Untreated, the condition leads to increasingly weak legs in cats, and eventually malnutrition, ketoacidosis and/or dehydration, and death.
Leptin
When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more part of this process, particularly the JAK/STAT pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of STAT3 are obese and exhibit hyperphagia. The PI3K pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause POMC neurons to become insensitive to leptin through hyperpolarization.
The consumption of a high fructose diet from birth has been associated with a reduction in leptin levels and reduced expression of leptin receptor mRNA in rats. Long-term consumption of fructose in rats has been shown to increase levels of triglycerides and trigger leptin and insulin resistance, however, another study found that leptin resistance only developed in the presence of both high fructose and high fat levels in the diet. A third study found that high fructose levels reversed leptin resistance in rats given a high fat diet. The contradictory results mean that it is uncertain whether leptin resistance is caused by high levels of carbohydrates or fats, or if an increase of both, is needed.
GSTK1
The amount of expression of adiponectin has been observed to be related to diseases such as insulin resistance, obesity, and type 2 diabetes. Decreased amounts of the protein indicates that there is a higher probability of receiving said diseases. Because the GSTK1 is seen to play a role in the multimerization of adiponectin, this enzyme can regulate the concentration of adiponectin and thus enhance insulin sensitivity and protect against diabetes. Also, the GSTK1 gene is unregulated when it is inflicted with oxidative stress and are over expressed in many tumors leading to difficulties during cancer chemotherapy. Moreover, GSTK1 gene expression has been seen to increase significantly in correlation to drug resistance in tumor cells such as erythroleukemia and mammary adenocarcinoma suggesting that it, along with GSTP1 and GSTA4, could be responsible for the drug resistance.
Outline of diabetes
Diabetes mellitus – group of metabolic diseases in which a person has high blood sugar, either because the pancreas does not produce enough insulin, or because cells do not respond properly to the insulin that is produced, a condition called insulin resistance. The resultant high blood sugar produces the classical symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).
Insulin resistance
Hepatitis C also makes people three to four times more likely to develop type 2 diabetes and insulin resistance. In addition, "people with Hepatitis C who develop diabetes probably have susceptible insulin-producing cells, and probably would get it anyway, but much later in life. The extra insulin resistance caused by Hepatitis C apparently brings on diabetes at age 35 or 40, instead of 65 or 70."
Host–pathogen interaction
The main problem with pathogenic drug treatments in the modern world is drug resistance. Many patients don’t take the full treatment of drugs, leading to the natural selection of resistant bacteria. One example of this is methicillin-resistant "Staphylococcus aureus" (MRSA). Because of antibiotic overuse, only the bacteria which have developed genetic mutations to combat the drug can survive. This reduces drug effectiveness and renders many treatments useless.
Moxonidine
Effects on insulin resistance
Insulin resistance
Another factor that may promote insulin resistance is Leptin, a hormone produced from the ob gene and adipocytes. Its physiological role is to regulate hunger by alerting the body when it is full. From an adaptation perspective, it is possible that leptin resistance was favorable for survival during periods when food was scarce. Today however studies show that lack of leptin causes severe obesity and is strongly linked with insulin resistance. Leptin replacement in mice with obesity and diabetes has been found to quickly decrease glucose and insulin levels and can affect insulin sensitivity. Further research into the molecular mechanisms of these effects would be beneficial for increased understanding.
Diabetic ketoacidosis
As a result of the above mechanisms, the average adult with DKA has a total body water shortage of about 6 liters (or 100 mL/kg), in addition to substantial shortages in sodium, potassium, chloride, phosphate, magnesium and calcium. Glucose levels usually exceed 13.8 mmol/L or 250 mg/dL.
DKA is common in type 1 diabetes as this form of diabetes is associated with an absolute lack of insulin production by the islets of Langerhans. In type 2 diabetes, insulin production is present but is insufficient to meet the body's requirements as a result of end-organ insulin resistance. Usually, these amounts of insulin are sufficient to suppress ketogenesis. If DKA occurs in someone with type 2 diabetes, their condition is called "ketosis-prone type 2 diabetes". The exact mechanism for this phenomenon is unclear, but there is evidence both of impaired insulin secretion and insulin action. Once the condition has been treated, insulin production resumes and often the person may be able to resume diet or tablet treatment as normally recommended in type 2 diabetes.
Diabetes mellitus type 1
Data suggest that gliadin (a protein present in gluten) might play a role in the development of type 1 diabetes, but the mechanism is not fully understood. Increased intestinal permeability caused by gluten and the subsequent loss of intestinal barrier function, which allows the passage of pro-inflammatory substances into the blood, may induce the autoimmune response in genetically predisposed individuals to type 1 diabetes. There is evidence from experiments conducted in animal models that removal of gluten from the diet may prevent the onset of type 1 diabetes but there has been conflicting research in humans.
Diabetes mellitus
Type 1 diabetes mellitus is characterized by loss of the insulin-producing beta cells of the pancreatic islets, leading to insulin deficiency. This type can be further classified as immune-mediated or idiopathic. The majority of type 1 diabetes is of the immune-mediated nature, in which a T cell-mediated autoimmune attack leads to the loss of beta cells and thus insulin. It causes approximately 10% of diabetes mellitus cases in North America and Europe. Most affected people are otherwise healthy and of a healthy weight when onset occurs. Sensitivity and responsiveness to insulin are usually normal, especially in the early stages. Type 1 diabetes can affect children or adults, but was traditionally termed "juvenile diabetes" because a majority of these diabetes cases were found in children.
Chinmoy Sankar Dey
Dey's research has been focusing on the drug resistance of two diseases, leishmaniasis and diabetes. His work on insulin resistance included the development of an "in-vitro" model, which has potential applications in screening anti-diabetic drugs. The model, which involved insulin-resistant cultured skeletal muscle cells, earned him a US patent. Using the model in tandem with biochemical and gene silencing methodologies, he demonstrated that focal adhesion kinases and p38 mitogen-activated protein kinases could be used as possible drug targets. His team identified for the first time the apoptosis-like cell death in Type II topoisomerase and suggested the enzyme as a possible treatment protocol for Leishmaniasis. His findings were published in a 2005 article in "Molecular and Biochemical Parasitology" of Elsevier. He also proposed eIF4A, a member of a set of three related proteins, as a drug target to combat infection with "Leishmania donovani", a Miltefosine-resistant type of trypanosome causing leishmaniasis. His work on myogenesis and muscular dystrophy showed insulin‑mediated dephosphorylation of PTK2 (focal adhesion kinase) could be stopped by inhibiting the activity of the insulin receptor tyrosine kinase, which was a new discovery. His research has been documented in numerous articles; ResearchGate, an online repository of scientific articles, lists 90 of them. Besides this he has contributed chapters to two books, and his work has drawn citations from other researchers. James Watson, a recipient of the Nobel Prize in Physiology or Medicine in 1962, cited one of Dey's papers in his 2013 lecture at University of California, Los Angeles to commemorate the 60th anniversary of the discovery of double helical structure DNA, which was later published as an article in Lancet in 2014. He also holds a Patent Cooperation Treaty and his aforementioned US patent, as well as two Indian patents, and has guided students in their master's and doctoral studies.
Oneirophrenia
Oneirophrenic patients are resistant to insulin and when injected with glucose, these patients take 30 to 50% longer to return to normal glycemia. The meaning of this finding is not known, but it has been hypothesized that it may be due to an insulin antagonist present in the blood during psychosis. However, there is currently no known treatment for oneirophrenia.
Dog leukocyte antigen
In 1974 J. Nerup and others discovered that there is a link between diabetes and MHC genes. Dog leukocyte antigen has been found to be the genetic component associated with canine diabetes. The common alleles/haplotypes found in diabetes prone breeds (Samoyed, Carin Terrier, and Tibetan Terrier) are DLA DBR1*009, DQA1*001, and DQB1*008. The DLA DQA1 alleles code for an arginine amino acid at position 55 in region two, this increases the risk of developing diabetes in dog as arginine is a positive amino acid which can impair antigen binding. This allele is also associated with hypothyroidism which implies that this allele increases susceptibility for endocrinopathic immune-mediated diseases. It is possible that the link discovered between DLA associations and diabetes could be due to "makers" of susceptibility and that the true reason for susceptibility lies elsewhere in the genome. It could be associated with particular DLA alleles/haplotypes or caused by the strong linkage disequilibrium.
Diabetes management
The main goal of diabetes management is, as far as possible, to restore carbohydrate metabolism to a normal state. To achieve this goal, individuals with an absolute deficiency of insulin require insulin replacement therapy, which is given through injections or an insulin pump. Insulin resistance, in contrast, can be corrected by dietary modifications and exercise. Other goals of diabetes management are to prevent or treat the many complications that can result from the disease itself and from its treatment.
Epigenetics of diabetes Type 2
The defects in pancreatic beta cell function and insulin resistance in peripheral tissues were thought to be the result of impaired ATP production from reduced oxidative phosphorylation. It was found that the mRNA expression of PPARGC1A was markedly reduced in pancreatic islets from type 2 diabetic donors compared with that of non-diabetic donors. Using bisulfite testing, it was also found that there was an approximately twofold increase in DNA methylation of the PPARGC1A promoter of human islet cells from diabetics as compared to non-diabetic human islet cells. This means that expression from the PPARGC1A genes were turned down in the diabetic patients. Further testing revealed that the more PPARGC1A was expressed, the more insulin was released from the islets, and as expected, in diabetic patients there was less PPARGC1A expressed and also less insulin secreted. This data supports the idea that PPARGC1A expression is reduced in animal models of diabetes and human diabetes and is associated with impaired insulin secretion.
HIV drug resistance
HIV drug resistance occurs when microevolution causes virions to become tolerant to antiretroviral treatments (ART). ART can be used to successfully manage HIV infection, but a number of factors can contribute to the virus mutating and becoming resistant. Drug resistance occurs as bacterial or viral populations evolve to no longer respond to medications that previously worked. In the case of HIV, there have been recognized cases of treatment resistant strains since 1989, with drug resistance being a major contributor to treatment failure. While global incidence varies greatly from region to region, there has been a general increase in overall HIV drug resistance. The two main types of resistance, primary and induced, differ mostly in causation, with the biggest cause of resistance being a lack of adherence to the specific details of treatment. These newly created resistant strains of HIV pose a public health issue as they infect a growing number of people because they are harder to treat, and can be spread to other individuals. For this reason, the reaction to the growing number of cases of resistant HIV strains has mostly been to try to increase access to treatment and implement other measures to make sure people stay in care, as well as to look into the development of a HIV vaccine or cure.
Wnt signaling pathway
Diabetes mellitus type 2 is a common disease that causes reduced insulin secretion and increased insulin resistance in the periphery. It results in increased blood glucose levels, or hyperglycemia, which can be fatal if untreated. Since Wnt signaling is involved in insulin sensitivity, malfunctioning of its pathway could be involved. Overexpression of Wnt5b, for instance, may increase susceptibility due to its role in adipogenesis, since obesity and type II diabetes have high comorbidity. Wnt signaling is a strong activator of mitochondrial biogenesis. This leads to increased production of reactive oxygen species (ROS) known to cause DNA and cellular damage. This ROS-induced damage is significant because it can cause acute hepatic insulin resistance, or injury-induced insulin resistance. Mutations in Wnt signaling-associated transcription factors, such as TCF7L2, are linked to increased susceptibility.
Insulin resistance
The primary treatment for insulin resistance is exercise and weight loss. Research shows that a low-carbohydrate diet may help. Both metformin and thiazolidinediones improve insulin resistance, but are approved therapies only for type 2 diabetes, not for insulin resistance. By contrast, growth hormone replacement therapy may be associated with increased insulin resistance.
Genetic causes of diabetes mellitus type 1
Additionally, nearly 30% of Type I Diabetes patients are heterozygous for several HLA-DQ2 (specifically HLA-DQ2/DQ8) alleles. However, the HLA-DQ6 allele (HLA-DQA1*0102–DQB1*0602), if dominant, is responsible for partially preventing an organism from developing the disease. Therefore, these genetic features can be used to determine a patient's relative risk of developing the disease.
MTORC1
Furthermore, since insulin is a factor that is secreted by pancreatic beta cells upon glucose elevation in the blood, its signaling ensures that there is energy for protein synthesis to take place. In a negative feedback loop on mTORC1 signaling, S6K1 is able to phosphorylate the insulin receptor and inhibit its sensitivity to insulin. This has great significance in diabetes mellitus, which is due to insulin resistance.
Insulin resistance
At a molecular level, insulin resistance has been proposed to be a reaction to excess nutrition by superoxide dismutase in cell mitochondria that acts as an antioxidant defense mechanism. This link seems to exist under diverse causes of insulin resistance. It also is based on the finding that insulin resistance may be reversed rapidly by exposing cells to mitochondrial uncouplers, electron transport chain inhibitors, or mitochondrial superoxide dismutase mimetics.
Evolutionary mismatch
Obesity is one consequence of mismatched genes. Known as "metabolic syndrome", this condition is also associated with other health concerns, including insulin resistance, where the body no longer responds to insulin secretion, so blood glucose levels are unable to be lowered, which can lead to type 2 diabetes.
Resistin
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. It was called "resistin" because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, rats, and mice). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.
Gestational diabetes
Insulin resistance is a normal phenomenon emerging in the second trimester of pregnancy, which in cases of GDM progresses thereafter to levels seen in a non-pregnant person with type 2 diabetes. It is thought to secure glucose supply to the growing fetus. Women with GDM have an insulin resistance that they cannot compensate for with increased production in the β-cells of the pancreas. Placental hormones, and to a lesser extent increased fat deposits during pregnancy, seem to mediate insulin resistance during pregnancy. Cortisol and progesterone are the main culprits, but human placental lactogen, prolactin and estradiol contribute, too. Multivariate stepwise regression analysis reveals that, in combination with other placental hormones, leptin, tumor necrosis factor alpha, and resistin are involved in the decrease in insulin sensitivity occurring during pregnancy, with tumor necrosis factor alpha named as the strongest independent predictor of insulin sensitivity in pregnancy. An inverse correlation with the changes in insulin sensitivity from the time before conception through late gestation accounts for about half of the variance in the decrease in insulin sensitivity during gestation: in other words, low levels or alteration of TNF alpha factors corresponds with a greater chance of, or predisposition to, insulin resistance or sensitivity.
Cross-resistance
Cross-resistance is the tolerance to a usually toxic substance as a result of exposure to a similarly acting substance. It is a phenomenon affecting e.g. pesticides and antibiotics. As an example rifabutin and rifampin cross react in the treatment of tuberculosis. This sort of resistance is also seen against drugs involved with the treatment of HIV. Drugs ending with "- ine" and "-inavir" are the most common.
Resistin
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion. It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide, which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation, which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance. Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
Diabetes mellitus type 2
Threshold for diagnosis of diabetes is based on the relationship between results of glucose tolerance tests, fasting glucose or HbA and complications such as retinal problems. A fasting or random blood sugar is preferred over the glucose tolerance test, as they are more convenient for people. HbA has the advantages that fasting is not required and results are more stable but has the disadvantage that the test is more costly than measurement of blood glucose. It is estimated that 20% of people with diabetes in the United States do not realize that they have the disease.
Epigenetics of diabetes Type 2
Studies in 2011 have shown that insulin resistance (IR), the hallmark of type 2 diabetes, may also involve epigenetic control as a contributing factor. Promoter methylation of the mitochondrial transcription factor A(TFAM) gene, an important gene essential for mitochondrial DNA maintenance, was associated with IR in adolescents. A possible link between DNA methylation and insulin resistance was shown through monozygotic twin comparisons and bisulfite pyrosequencing to measure the global DNA methylation of Alu repeats in peripheral blood leukocytes. Alu elements are known to create genomic instability and affect gene expression, and have been implicated in numerous human diseases. Epigenetic alterations arising during the lifetime of monozygotic twins in Alu repeats resulted in an increase in genomic s instability, and consequently cause insulin resistance and type 2 diabetes. show that methylation levels at all four CpG sites displayed an increase in Alu methylation. This study provides the first evidence that alteration in global DNA hypermethylation is associated with increased risk of IR independent of established risk factors. Because epigenetic modifications are possibly reversible, this research suggests the potential for lifestyle or therapeutic interventions for insulin resistance.
Diabetic angiopathy
Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.
As insulin is required for glucose uptake, hyperglycemia in diabetes mellitus does not result in a net increase in intracellular glucose in most cells. However, chronic dysregulated blood glucose in diabetes is toxic to cells of the vascular endothelium which passively assimilate glucose. That is, cells in which insulin is not required for intercellular transport of glucose, most-notably the pericytes of the microvasculature. In addition to direct glucose-induced damage by (e.g.) glycation, pericytes express enzymes which convert glucose into osmologically-active metabolites such as sorbitol leading to hypertonic cell lysis.
Diabetes mellitus type 1
Complications of poorly managed type 1 diabetes mellitus may include cardiovascular disease, diabetic neuropathy, and diabetic retinopathy, among others. However, cardiovascular disease as well as neuropathy may have an autoimmune basis, as well. Women with type 1 DM have a 40% higher risk of death as compared to men with type 1 DM. The life expectancy of an individual with type 1 diabetes is 11 years less for men and 13 years less for women. People with type 1 diabetes are higher risk for other autoimmune diseases, such as autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and lupus.
Mark Mattson
Mattson’s work has revealed mechanisms by which diabetes adversely affects hippocampal plasticity and cognitive function. He showed that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Changes in hippocampal plasticity and function in both models were reversed when normal physiological levels of corticosterone were maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoid-mediated deficits in neurogenesis and synaptic plasticity. In a related study, Mattson showed that rats fed with a high-fat, high-glucose diet supplemented with fructose corn syrup exhibit alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for 8 months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced long-term potentiation at Schaffer collateral—CA1 synapses. These changes occurred concurrently with reductions in levels of BDNF in the hippocampus. Mattson also investigated whether manipulations that enhance neurotrophin levels will also restore neuronal structure and function in diabetes. He found that running wheel activity, caloric restriction, or the combination of the two treatments increased levels of BDNF in the hippocampus of diabetic mice. Enhancement of hippocampal BDNF was accompanied by increases in dendritic spine density on the secondary and tertiary dendrites of dentate granule neurons. These studies suggest that diabetes exerts detrimental effects on hippocampal structure, and that this state can be attenuated by increasing energy expenditure and decreasing energy intake. The implications of these findings for cognitive aging are clear – dietary moderation and regular exercise will enhance cognitive function.
Insulin resistance
The presence of insulin leads to a kind of insulin resistance; every time a cell is exposed to insulin, the production of GLUT4 (Glucose transporter type 4) on the membrane of the cell decreases somewhat. In the presence of a higher than usual level of insulin (generally caused by insulin resistance), this down-regulation acts as a kind of positive feedback, increasing the need for insulin. Exercise reverses this process in muscle tissue, but if it is left unchecked, it may contribute to insulin resistance.
Complications of diabetes mellitus
It is more accurate to note that iatrogenic hypoglycemia is typically the result of the interplay of absolute (or relative) insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine are the primary glucose counterregulatory factors that normally prevent or (more or less rapidly) correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation.
Blood sugar regulation
Diabetes mellitus type 1 is caused by insufficient or non-existent production of insulin, while type 2 is primarily due to a decreased response to insulin in the tissues of the body (insulin resistance). Both types of diabetes, if untreated, result in too much glucose remaining in the blood (hyperglycemia) and many of the same complications. Also, too much insulin and/or exercise without enough corresponding food intake in diabetics can result in low blood sugar (hypoglycemia).
Hyperglycemia
In diabetes mellitus, hyperglycemia is usually caused by low insulin levels (Diabetes mellitus type 1) and/or by resistance to insulin at the cellular level (Diabetes mellitus type 2), depending on the type and state of the disease. Low insulin levels and/or insulin resistance prevent the body from converting glucose into glycogen (a starch-like source of energy stored mostly in the liver), which in turn makes it difficult or impossible to remove excess glucose from the blood. With normal glucose levels, the total amount of glucose in the blood at any given moment is only enough to provide energy to the body for 20–30 minutes, and so glucose levels must be precisely maintained by the body's internal control mechanisms. When the mechanisms fail in a way that allows glucose to rise to abnormal levels, hyperglycemia is the result.
Gluconeogenesis
Global control of gluconeogenesis is mediated by glucagon ("released when blood glucose is low"); it triggers phosphorylation of enzymes and regulatory proteins by Protein Kinase A (a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis. Insulin counteracts glucagon by inhibiting gluconeogenesis. Type 2 diabetes is marked by excess glucagon and insulin resistance from the body. Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body. The anti-diabetic drug metformin reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit glucogeneogenesis due to insulin resistance.
Epigenetics of diabetes Type 2
Studies have shown that the islet dysfunction and development of diabetes in rats is associated with epigenetic silencing via DNA methylation of the gene Pdx1 promoter, which produces a key transcription factor that regulates beta-cell differentiation and insulin gene expression. Silencing at this promoter decreases the amount of beta-cells produced which leads to insulin resistance and the inability of the beta-cells to produce an important peptide that prevents vascular deterioration and neuropathy caused from vascular inflammatory responses.
Gestational diabetes
The precise mechanisms underlying gestational diabetes remain unknown. The hallmark of GDM is increased insulin resistance. Pregnancy hormones and other factors are thought to interfere with the action of insulin as it binds to the insulin receptor. The interference probably occurs at the level of the cell signaling pathway beyond the insulin receptor. Since insulin promotes the entry of glucose into most cells, insulin resistance prevents glucose from entering the cells properly. As a result, glucose remains in the bloodstream, where glucose levels rise. More insulin is needed to overcome this resistance; about 1.5–2.5 times more insulin is produced than in a normal pregnancy.
Diabetes mellitus
Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders in which there are high blood sugar levels over a prolonged period. Symptoms of high blood sugar include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can cause many complications. Acute complications can include diabetic ketoacidosis, hyperosmolar hyperglycemic state, or death. Serious long-term complications include cardiovascular disease, stroke, chronic kidney disease, foot ulcers, and damage to the eyes.
Diabetes is due to either the pancreas not producing enough insulin, or the cells of the body not responding properly to the insulin produced. There are three main types of diabetes mellitus:
Prevention and treatment involve maintaining a healthy diet, regular physical exercise, a normal body weight, and avoiding use of tobacco. Control of blood pressure and maintaining proper foot care are important for people with the disease. Type 1 DM must be managed with insulin injections. Type 2 DM may be treated with medications with or without insulin. Insulin and some oral medications can cause low blood sugar. Weight loss surgery in those with obesity is sometimes an effective measure in those with type 2 DM. Gestational diabetes usually resolves after the birth of the baby.
, an estimated 415 million people had diabetes worldwide, with type 2 DM making up about 90% of the cases. This represents 8.3% of the adult population, with equal rates in both women and men. , trends suggested the rate would continue to rise. Diabetes at least doubles a person's risk of early death. From 2012 to 2015, approximately 1.5 to 5.0 million deaths each year resulted from diabetes. The global economic cost of diabetes in 2014 was estimated to be billion. In the United States, diabetes cost $245 billion in 2012.
The classic symptoms of untreated diabetes are unintended weight loss, polyuria (increased urination), polydipsia (increased thirst), and polyphagia (increased hunger). Symptoms may develop rapidly (weeks or months) in type 1 DM, while they usually develop much more slowly and may be subtle or absent in type 2 DM.
Diabetes mellitus type 2
Type 2 diabetes is typically a chronic disease associated with a ten-year-shorter life expectancy. This is partly due to a number of complications with which it is associated, including: two to four times the risk of cardiovascular disease, including ischemic heart disease and stroke; a 20-fold increase in lower limb amputations, and increased rates of hospitalizations. In the developed world, and increasingly elsewhere, type 2 diabetes is the largest cause of nontraumatic blindness and kidney failure. It has also been associated with an increased risk of cognitive dysfunction and dementia through disease processes such as Alzheimer's disease and vascular dementia. Other complications include acanthosis nigricans, sexual dysfunction, and frequent infections.
Nephrogenic diabetes insipidus
Although they shared a name, diabetes mellitus and diabetes insipidus are two separate conditions. Both cause excessive urination (hence the similarity in name), but whereas diabetes insipidus is a problem with the production of antidiuretic hormone (central diabetes insipidus) or the kidneys' response to antidiuretic hormone (nephrogenic diabetes insipidus), diabetes mellitus causes polyuria via osmotic diuresis, due to the high blood sugar leaking into the urine, taking excess water along with it.
Diabetes mellitus type 1
In type 1, pancreatic beta cells in the islets of Langerhans are destroyed, decreasing endogenous insulin production. This distinguishes type 1's origin from type 2. Type 2 diabetes is characterized by insulin resistance, while type 1 diabetes is characterized by insulin deficiency, generally without insulin resistance. Another hallmark of type 1 diabetes is islet autoreactivity, which is generally measured by the presence of autoantibodies directed towards the beta cells.
Abdominal obesity
Insulin resistance is a major feature of diabetes mellitus type 2 (T2DM), and central obesity is correlated with both insulin resistance and T2DM itself. Increased adiposity (obesity) raises serum resistin levels, which in turn directly correlate to insulin resistance. Studies have also confirmed a direct correlation between resistin levels and T2DM. And it is waistline adipose tissue (central obesity) which seems to be the foremost type of fat deposits contributing to rising levels of serum resistin. Conversely, serum resistin levels have been found to "decline" with decreased adiposity following medical treatment.
Kent Holtorf
Leptin resistance is described as a condition in which overweight individuals are unable to respond to the hormone’s signals appropriately, leading to a starvation response in the body as well as hypothyroid symptoms at the cellular level where they are more difficult to detect. Holtorf treats leptin resistance in patients with a class of medications that are typically reserved for controlling blood sugar levels in diabetics.
Insulin resistance
Insulin resistance and type 2 diabetes are associated with excess body weight. A possible explanation is that both insulin resistance and obesity often have the same cause, systematic overeating, which has the potential to lead to insulin resistance and obesity due to repeated administration of excess levels of glucose, which stimulate insulin secretion; excess levels of fructose, which raise triglyceride levels in the bloodstream; and fats, which may be absorbed easily by the adipose cells, and tend to end up as fatty tissue in a hypercaloric diet. Some scholars go as far as to claim that neither insulin resistance, nor obesity really are metabolic disorders "per se", but simply adaptive responses to sustained caloric surplus, intended to protect bodily organs from lipotoxicity (unsafe levels of lipids in the bloodstream and tissues): "Obesity should therefore not be regarded as a pathology or disease, but rather as the normal, physiologic response to sustained caloric surplus... As a consequence of the high level of lipid accumulation in insulin target tissues including skeletal muscle and liver, it has been suggested that exclusion of glucose from lipid-laden cells is a compensatory defense against further accumulation of lipogenic substrate."
Diabetes mellitus type 1
Diabetes mellitus type 1, also known as type 1 diabetes, is a form of diabetes mellitus in which very little or no insulin is produced by the pancreas. Before treatment this results in high blood sugar levels in the body. The classic symptoms are frequent urination, increased thirst, increased hunger, and weight loss. Additional symptoms may include blurry vision, feeling tired, and poor wound healing. Symptoms typically develop over a short period of time.
The cause of type 1 diabetes is unknown. However, it is believed to involve a combination of genetic and environmental factors. Risk factors include having a family member with the condition. The underlying mechanism involves an autoimmune destruction of the insulin-producing beta cells in the pancreas. Diabetes is diagnosed by testing the level of sugar or glycated hemoglobin (HbA1C) in the blood. Type 1 diabetes can be distinguished from type 2 by testing for the presence of autoantibodies.
There is no known way to prevent type 1 diabetes. Treatment with insulin is required for survival. Insulin therapy is usually given by injection just under the skin but can also be delivered by an insulin pump. A diabetic diet and exercise are important parts of management. If left untreated, diabetes can cause many complications. Complications of relatively rapid onset include diabetic ketoacidosis and nonketotic hyperosmolar coma. Long-term complications include heart disease, stroke, kidney failure, foot ulcers and damage to the eyes. Furthermore, complications may arise from low blood sugar caused by excessive dosing of insulin.
Type 1 diabetes makes up an estimated 5–10% of all diabetes cases. The number of people affected globally is unknown, although it is estimated that about 80,000 children develop the disease each year. Within the United States the number of people affected is estimated at one to three million. Rates of disease vary widely with approximately 1 new case per 100,000 per year in East Asia and Latin America and around 30 new cases per 100,000 per year in Scandinavia and Kuwait. It typically begins in children and young adults.
The classical symptoms of type 1 diabetes include: polyuria (increased urination), polydipsia (increased thirst), dry mouth, polyphagia (increased hunger), fatigue, and weight loss.
Insulin resistance
Resistant starch from high-amylose corn, amylomaize, has been shown to reduce insulin resistance in healthy individuals, in individuals with insulin resistance, and in individuals with type 2 diabetes. Animal studies demonstrate that it cannot reverse damage already done by high glucose levels, but that it reduces insulin resistance and reduces the development of further damage.