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Diabetes

A group of metabolic processes with hyperglycemia.

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Diabetes mellitus is a group of metabolic disorders in which the blood glucose is higher than normal levels, due to insufficiency of insulin release or improper response of cells to insulin, resulting in high blood sugar.

Aside from type I, type II and gestational diabetes mellitus the American Diabetes Association recognizes an additional 56 types of diabetes.

About 9% of the world’s s population has diabetes.
 
Prevalence in the US is greater than 14%.
Affects more than 450 million people worldwide.
Management of diabetes cost about 10% of the global health expenditure, $760 billion US.

The relation between metabolic disturbances in diabetes and vascular damage is approximately linear.

Associated with eight core defects: decreased insulin secretion, decreased incretin effect, increased lipolysis, increased glucose reabsorption, decreased glucose uptake, neurotransmitter dysfunction, increased hepatic glucose production, and increased glucagon secretion.

Every year about 234,051 Americans die due to diabetes (type I or II) or diabetes-related complications, with 69,071 having it as the primary cause of death.

 

The incidence of adverse cardiovascular events among persons with diabetes is triple that among persons without diabetes.

 

The incidence of adverse cardiovascular events rises with increasing duration of diabetes, increasing hemoglobin A-1 C, increasing urinary albumin-to-creatinine ratio, the presence of kidney dysfunction, a history of cardiovascular disease, and the presence of other cardiovascular risk factors.

The relative risk of cardiovascular disease in type 2 diabetes increases approximate 16% for every percentage point increase in hemoglobin A-1 C.

Diabetes is a coronary artery disease equivalent with a 2-4 fold increase for its development and the prevalence of acute coronary syndrome is as high as 20% at seven years a follow up.

Type 2 diabetes is one of the most prevalent chronic conditions in older adults.

Type two diabetes accounts for 90 to 95% of cases and is characterized by progressive loss of adequate insulin secretion, usually with insulin resistance.

Type 2 DM is among the most common metabolic disorders, with a prevalence ranging from 2.4 to 14.8% in the general population.

Approximately 25%-30% of older adults in the United States have diabetes and another 25%-30% have glucose intolerance, a prediabetic state.

The BLSA (Baltimore Longitudinal Study of Aging) showed

a progressive decline in glucose tolerance from the third through the ninth decade of life.

Although the exact etiology is unknown, age-dependent decreases in pancreatic ?-cell function and

insulin sensitivity are believed to play important roles in the deterioration of glucose homeostasis

that occurs with advancing age.

Risk factors for the development of diabetes are: elevated levels of triglycerides, elevated blood pressure, elevated BMI, and positive family history.

Plasma levels of branched-chain amino acids: leucine, valine, and isoleucine are consistently elevated in patients with insulin resistance and diabetes.

Type two diabetes affects more than one third of a billion people worldwide and is leading cause of end stage renal disease, non-traumatic loss of limb, and blindness and estimated worldwide health care cost exceeding a half trillion dollars.

In the United States $245 billion every year is attributed to diabetes. 

 

 

Individuals diagnosed with diabetes have 2.3 times the health care costs as individuals who do not have diabetes. 

 

 

One in ten health care dollars are spent on individuals with type 1 and 2 diabetes.

 

Other types of nonimmune mediated injury to beta cells include: cystic fibrosis, acute or chronic pancreatitis, partial or complete pancreatic resection,and hemochromatosis.

The degree of diabetes is usually proportional to the amount of injury to the pancreatic Beta cell mass.

At the time of diagnosis an average of only 50% of beta cell function remains.

Using data from more than 25 studies and 1 million patients, investigators concluded each 1-year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% lower risk of all-cause mortality, macrovascular disease, and microvascular disease, respectively.

Ranked as the seventh leading cause of death in the U.S. in 2006.

Estimated 422 million people worldwide live with diabetes, and half are undiagnosed.

29 million adults (1 in 11) have type 2 DM and another 86 million have prediabetes.

Approximately 40% of US adults have insulin resistance.

Prevalence in adults over the age of 65 years is 26%.

Approximately 1 in 11 adults worldwide have type 2 DM.

One in nine healthcare dollars expended on diabetes and its complications.

The main complications of diabetes are microvascular disease (retinopathy, neuropathy, and the frothy) and macrovascular disease (coronary heart disease, peripheral vascular disease, and cerebrovascular disease).
Annual per capita healthcare expenditures are 2.3 times higher for people with diabetes compared with those without diabetes.

In 2014 type two diabetes affected approximately 9.3% of US adults and 36.4% are undiagnosed.

Accounts for almost 200,000 deaths annually worldwide.

Almost 14% of healthcare expenditures in US come from diabetes and more than 50% is due to complications of the disease.

Myocardial infarction is the most common cause of death in patients with diabetes.The incidence of diabetes can be reduced by as much as 50% by lifestyle and pharmacological interventions.

Patients with type two diabetes are at increased risk of developing atrial fibrillation , and patients with the combination of atrial fibrillation and diabetes are at high risk for stroke.

Bariatric surgery reduces the long-term incidence to diabetes by 80% percent in the Swedish Obese Subject study.

In 2007 was estimated that diabetes was the underlying cause of more than 70,000 deaths, and a contributing factor to an additional 160,000 deaths in the US.

Most patients with diabetes do not have their hemoglobin A-1 C., blood pressure or low-density lipoprotein-cholesterol under control.

Third leading cause of death in women and fourth in men (Loyd-jones D et al).

More than 40% of adults with diabetes are older than 65 years of age.

There is a strong association between diabetes and frailty.

For men who consumed less than 2 servings of vegetables per day are 162% more likely to develop diabetes than those who consume 2 or more servings per day. 

Women with uncontrolled diabetes had 2.27 times the risk of mortality than did patients without diabetes, and women with undiagnosed diabetes had a 61% increase.

Total number of affected people with type two diabetes is more than 370 million people globally.

Its prevalence is increasing worldwide, and is estimated at 8.8% in 2017, with a slightly higher prevalence among men at 9.1%, than among women 8.4%.

Meta-analyses show that redmeat and processed meat are associated with an increased risk of diabetes.

Hyperglycemia results from defects in insulin secretion, insulin action, or most commonly, both.

Chronic hyperglycemia and other metabolic abnormalities lead to damage in eyes, kidneys, nerves and blood vessels.

Glycemic fluctuations and postprandial glucose excursion are associated with the presence in severity of coronary artery disease in patients with type two diabetes.

Elevated glucose outside the cells in diabetes is associated with an intracellular deficit of glucose.

Keeping blood sugar levels under 100 mg/dL before eating and under 180 mg/dL after eating, people with diabetes can significantly reduce their risk of adverse effects from the disease.

Since glucose catabolism is a major sorts of energy for cellular processes, in diabetes energy requirements must be met by drawing on protein and fat reserves-therefore catabolism of protein and fat are increased, leading to increased ketone production.

Deficient intracellular glucose utilization in the satiety area of the hypothalamus may be responsible for hyperphagia in diabetes.

Intracellular glucose deficit seen in diabetes leads to glycogen depletion, and glycogen stores are decreased in the liver and skeletal muscles.

The rate at which amino acids are metabolize to CO2 and H2O is increased in diabetes.

The rate of conversion of amino acids to glucose in the liver is increased in diabetes.

Glucagon stimulates gluconeogenesis, and hyperglucagonemia is generally present in diabetes.

Type I form of the disease is the sixth-leading cause of death and the most common chronic disease in the U.S.

Type 1 diabetes accounts for 10% of diabetic cases in the US.

Estimated 25 million people in the United States have diabetes, 8.3% of US population, with type 2 accounting for 90-95% of all cases.

US cost of diabetes $174 billion including $116 billion in direct medical costs and $58 billion in indirect cost such as disability, loss of work and premature mortality.

Older patients with type 2 diabetes have twice the prevalence of disability in mobility related activities, as compared with those without the disease, and increased body mass index further increases in risk.

Incidence doubled in last 15 years.

Incidence highest in 65-79 age group.

Adiposity recognized risk factor for young and middle aged adults.

Incidence of type 2 diabetes in children and adolescents is increasing as rates of childhood obesity have increased.

The rate of new cases of type II diabetes among those younger than 20 years 8.5 per hundred thousand.

The estimated prevalence of diabetes among children and adolescents has increased significantly for both type one and type two diabetes.

Approximately 20,000 children in the US is a are affected by type II diabetes.

Diabetic ketoacidosis is observed in more than 20% of children at the onset of type I diabetes and may be severe or even fatal in undiagnosed or miss diagnosed patients.

The possibility of diagnosing type I diabetes an early disease stage could reduce morbidity.

Among adults 65 and above, overall and central adiposity, and weight gain during middle age and after age 65 associated with increased risk of diabetes (Cardiovascular Health Study).

Increase body mass index is associated with diabetes at the population level, but it does not adequately discriminate the risk of diabetes among obese individuals.

Blood pressure levels are on average higher among individuals with diabetes, and increased BP is an established risk factor for diabetics.

In patients with type two diabetes blood pressure lowering improves mortality and clinical outcomes among those with baseline blood pressure 140 mmHg and greater, supporting the use of medications for hypertension.

Hypertension and glucose levels are both significant risk factors for heart disease in young adults with type 1 diabetes (T1D).

Young adult patients with DM1, hypertension are twice as likely to develop coronary artery disease (CAD) compared to patients with normal blood pressure.

Many obese persons are resistant to the development of metabolic disease.

Among parous women with type 2 DM, approximately one-third had a history of gestational DM.

In a meta-analysis of 12 studies involving 226,652 patients there was a 9% increased risk of developing diabetes among shift work jobs.

DECODE study found impaired glucose as determined by two hour postprandial glucose concentration increased the risk for cardiovascular events and death.

Adipose tissue dysfunction characterized by ectopic fat deposition in abdominal organs and liver, inflammatory and adipokine dysregulation and insulin resistance and may be an important mediator of the development of diabetes rather than total fat mass in obese individuals.

Prediabetes is also a pro- inflammatory state, and the presence of inflammation in the prediabetic

Similarly, prediabetes is also a pro- inflammatory state, and the presence of inflammation in the prediabetic state predicts the onset of future diabetes.

The mechanism linking inflammation with insulin resistance is believed to be partly a result of excess glucose- and free fatty acid-induced stress to insulin-sensitive tissues, particularly adipose and liver, leading to the production of inflammatory cytokines such as TNF?, interleukin-1?, and IL-6, which further promote inflammation in other tissues, including muscle and islet cells.

The above Cardiovascular Health Study was a prospective analysis of 4193 adult male and female patients over the age of 65 years: weight control remains important in reducing diabetes risk among adults 65 years of age and older.

Type 1 diabetes is more common in childhood, but can occur at anytime of life.

Type 1 diabetes environmental drivers implicate: infectious causes, improved sanitation, use of antibiotics, increased Cesarean deliveries, low vitamin D levels, and increased gluten consumption.

Estimated between 1.2 and 2.4 million individuals in the US have type 1 diabetes.

Patients with type 1 diabetes are at increased risk for celiac disease, an immune mediated disease, characterized by destruction of small bowel mucosa with gluten exposure.

Most patients present with type 1 diabetes in childhood.

Type I DM. an autoimmune disease can be detected in asymptomatic patients by presence of islet cell autoantibodies that develop in children, with peak incidence at about 1 year of age.

Insulin autoantibodies in type I DM are the first to appear, followed by autoantibodies to other antigens before onset of diabetes.

Type I diabetes is characterized by autoantibodies against pancreatic islet cells in the pre-clinical period.

Most children with autoantibodies against two or more major islet autoantigens will develop overt diabetes.

CD4+T cells directed against pro insulin and CD8+ T cell directed against insulin seen in type I DM.

Incidence of type I diabetes is increasing.

Diabetes type I usually associated with preclinical phase with autoantibodies to antigens of the pancreatic beta cells.

Circulating islet autoantibodies ssociated with increased risk of developing type I diabetes.

Risk of diabetes type I dependent on beta cell function and diversity and titer of autoantibodies, with greater risk associated with 2 or more autoantibodies and impaired glucose tolerance.

The risk of developing diabetes is dependent on beta cell function and the diversity and titer of autoantibodies, with the greatest risk associated with two more autoantibodies and impaired glucose tolerance.

Nearly 18,000 young people are diagnosed with type one diabetes every year.

The majority of children at risk of type one diabetes with multiple islet autoantibodies progress to diabetes over 15 years (Ziegler AG et al).

In adolescents and children with type one diabetes 24% are overweight and additional 15% are obese.

Annual increase of type I diabetes in the last 4 decades associated with 2.8-3.0% annual increases globally (Diamond Project Group, Onkamo P).

Adults misdiagnosed as having type II, rather than type I will be expected to have a very limited or transient response to oral agents and will progress rapidly to insulin therapy.

Type 1 diabetics have an absolute deficiency of insulin, and therefore insulin and is the mainstay of treatment.

Type 1 DM is an autoimmune disease in 90% of the cases and idiopathic in <10%.

Type I DM usually associated with ketosis in the untreated state.

Type I DM associated with increased urination secondary to osmotic diuresis related to sustained hyperglycemia with loss of glucose, free water and electrolytes in the urine.

Type I DM with osmotic diuresis associated with a hyperosmolar state with blurred vision.

Type I DM commonly associated with weight loss despite normal or increased appetite, and this is due to depletion of water, glycogen, and triglycerides and subsequently reduced muscle mass as a result of amino acid diversion to form glucose and ketone bodies.

Type I DM osmotic diuresis associated with lowered plasma volume and can produce postural hypotension.

In type I diabetes total body potassium loss and generalized catabolism of muscle protein is associated with the generalized weakness.

Type I diabetes may be associated with initially with paresthesias, reflecting dysfunction of peripheral sensory nerves, which may improve with diabetic therapy as hyperglycemia comes under control.

Type I DM, most commonly arises in children and young adults with a peak incidence before school age and with a second spike around puberty.

Type I DM frequently found in families with a high prevalence of other autoimmune diseases.

Acutely decompensated diabetes diabetic keto acidosis and hyper eyes molar hyperglycemic stay or potentially life-threatening processes.

Acutely decompensated diabetes occurs when there is an acute insulin deficiency and low insulin/glucagon ratio in the liver.

When there is an acute insulin deficiency, ketosis and metabolic stress there is an increase in stress hormones, including glucagon, catecholamines, cortisol, and growth hormone,.

Patients with type 1 diabetes have a higher incidence of autoimmune diseases over their lifetime.

Monozygotic twins are not uniformly concordant for the development of type I DM.

Markers of autoimmunity in type I diabetes include: anti-islet, anti-glutamic acid decarboxylase-65 antibodies (anti-GAD), anti-tyrosine phosphatase (anti-IA2), and anti-insulin autoantibodies.

Five disease related auto-antibodies predict clinical manifestations of type I diabetes: islet cell anti-bodies, insulin autoantibodies, autoantiboies to glutamic acid decarboxylase, the tyrosine phosphatase-related insulinoma- associated2 molecule (IA2), and zinc transporter 8 (ZnT8).

The presence of two or more antibodies indicates a risk of 5200% for the development of type I diabetes over 5-10 years (Knip M).

Type 1 diabetes is sub classified as type IA, if autoimmune markers are positive and type IB if such markers are not present.

Approximately 90% of newly diagnosed patients type I diabetes will have at least one positive antibody titer.

Antibody titer positivity in type I will vary with age, duration of diabetes and ethnicity.

Antibody titers decreased with the duration of the illness and low levels of anti-insulin antibodies developed in almost all patients treated with insulin.

Anti-GAD data are positive in 70 to 80% of patients at the time of diagnosis of type I diabetes.

Anti-GAD antibodies or more commonly positive in adults who develop type I diabetes and generally remain positive.

Anti-insulin antibodies in type I diabetes on not reliably measured after initiation of insulin therapy (Notkins AL).

Beta cell auto-immunity may be induced early in life, as indicated by the incidence of type I diabetes is rising faster than it had previously been noted among children younger than five years of age.

Type I diabetes patients, family members are at an increased lifetime risk for developing Type I DM.

The child of a Type I diabetic mother has a 3% risk of developing Type I DM, and a 6% risk if the father has type I diabetes.

A sibling of a Type I diabetic has a risk of developing Type I DM related to the number of HLA types shared with the diabetic patient: one haplotype share is related to a 6% risk, with two shared haplotypes the risk is 12 to 25% and identical twins have a risk of 25 to 50%.

In a double-blind randomized trial 230 infants with HLA susceptibility to type I diabetes, and at least one family member with type I diabetes to receive a casein hydrolysate formula or a conventional, cow’s milk-based formula whenever the breast milk was not available during the first 6-8 months of life: dietary intervention had a long-lasting effect on markers of beta cell auto immunity with a hazard ratio for positivity for one or more autoantibodies was 0.54 compared to the control group (Knip M et al).

Use of insulin early in the treatment of type I diabetics diagnosed in adulthood increases their ability to make endogenous insulin (Linn T).

Direct costs for approximately $1 of every $10 in U.S. health care costs and when indirect costs are added the annual cost is about 174 billion dollars (2008).

Approximately 2 million Americans have Type I diabetes mellitus.

Type I DM is a catabolic process with virtually absent circulating insulin, elevated plasma glucagon levels, and pancreatic beta cells that fail to respond to insulinogenic stimuli.

In type I diabetes there is loss of pancreatic beta-cells and therefore an absolute insulin deficiency, and because the disease does not affect insulin sensitivity, patients typically require small doses of insulin to maintain glucose control.

Highest incidence of immune mediated type I DM is in Scandinavia and northern Europe, with an annual incidence as high as 40 per hundred thousand children, while in the United States the annual incidence of type I diabetes averages 16 per hundred thousand.

The lowest incidence of type I diabetes is in China and parts of South America with less than one case per hundred thousand per year.

It is estimated that Type I DM,approximately 1/3 of the disease susceptibility is related to genetic factors, two thirds of cases are related to environmental factors.

In type I DM genes related to the HLA locus contribute about 40% of the genetic risk.

Approximately 95% of patients with type I DM have HLA-DR3 or HLA-DR4, compared to 45-50% of Caucasian controls.

HLA-DQB1*0302 in the HL a-DR4 is a marker for type I DM susceptibility, while HLA-DQB1*0602 is a protective gene and often found in DR4 controls.

About 10% of genetic risk in type I diabetes is found at the 5′ polymorphic region of the insulin gene resulting in depletion of insulin specific T lymphocytes in the fineness gland.

Prevalence of undiagnosed diabetes approximates 40% of the US diabetic population.

Estimated that about 5% of the US population over the age of 20 has diabetes, but is unaware of the diagnosis.

Prevalence has increased from 0.9% in 1958 to 4.4% in 2000, and projected to be 7.2% by 2050.

More than 10% of US adults have diabetes and the prevalence is much higher in adults over the age of 60 years at 23% (CDC).

National Health and Nutrition Examination Survey data from 2005-2006 determined the prevalence in ambulatory individuals 20 years and older to be 12.9% (Cowie CC).

In the above study an additional 29.5% had impaired fasting plasma glucose levels, or impaired glucose tolerance, or both, indicating that 42.4% of the US population aged 20 years or older had some degree of abnormal glucose control.

A large group of individuals have glucose levels not sufficiently elevated to be considered diabetic, but are too high to be considered normal.

Patients with fasting glucose levels between 100 and 125 mg per deciliter or a two-hour postprandial glucose reading of 140-199 mg per deciliter are considered to have impaired fasting glucose or impaired glucose tolerance, respectively: these individuals have normal hemoglobin A1C. levels, and/or virtually normoglycemic but at high risk to develop overt diabetes.

Patients with hemoglobin A1C results of 5.7-6.4% are conceded to be at high risk to develop diabetes, and therefore have prediabetes.

Patients with a hemoglobin A1C of 6-6.5% are at particularly high risk to develop diabetes.

In a meta- analysis of the use of aspirin as a primary prevention of cardiovascular events in people with diabetes, no clear benefit has been established (De Berardis G).

Low dose aspirin recommended by ADA for adults with diabetes and no previous cardiovascular disease but with a 10 year risk of CV disease events greater than 10% and do not have an increased risk forbleeding (Pignone M et al).

Among patients with diabetes reducing glycemia results in a small reduction in risk of major macrovascular events (Turnbull FM).

Diabetics exhibit abnormal heart rate response to exercise, which are independently predictive of reduced long term survival.

Glucose levels after a glucose load are more closely associated with cardiovascular risk than are fasting glucose levels.

Mediterranean diet supplemented with extra-virgin olive oil results in a 40% relative reduction in diabetes risk compared with the control group in individuals 55-80 years (PREDIMED).

Decreasing postprandial glucose levels with acarbose, a alpha-glucosidase inhibitor, shown to decrease risk of myocardial infarction among individuals with glucose intolerance (Chiasson JL).

Type I accounts for 10% of cases of diabetes.

In type 1 diabetics 35-40% of patients regularly have episodes of severe hypoglycemia, necessitating third-party assistance.

About 25% of type 1 diabetics have a blunting of the symptoms of hypoglycemia, hypoglycemic unawareness, and such patients have a risk of severe hypoglycemia that is increased by a factor of up to six fold.

Hypoglycemia is the single greatest barrier to achieving glycemic control in patients with diabetes.

More than 24 million people in the U.S. affected with 90% having type 2 diabetes.

Eating nuts may decrease the risk of cardiovascular disease (CVD) and death in people with type 2 diabetes.

Currently, 285 million people worldwide have type II diabetes.

Type I diabetes results from Beta cell destruction, usually leading to insulin deficiency.

Type II diabetes results from a progressive insulin secretory defect on the background of insulin resistance.

Resistance exercise is associated with a lower risk of type two diabetes in both men and women.

The primary treatment goal for type II diabetes is to achieve and maintain optimal glycemic control, to reduce microvascular, and possibly macrovascular complications.

Approximately 52-59% of all patients with type II diabetes in the US achieve hemoglobin A-1 C levels below 7%.

Blood glucose levels in patients with Type II DM can fluctuate dramatically throughout the day despite achieving HgbA1c targets.

Glycemic fluctuations may be associated with cardiovascular complications.

Mechanisms for increased cardiovascular complications due to glycemic fluctuations include: endothelial dysfunction, increased oxidative stress, and enhanced pro inflammatory and procoagulant activity.

Type II diabetes not associated with autoimmune destruction of beta cells, although beta cell mass may be reduced.

Type II diabetics maintain euglycemia as long as beta cells secrete higher amounts of insulin, but over time insulin levels decline as beta cells decrease and their secretory capacity diminishes.

A 50% or greater decrease in maximum beta cell function at diagnosis.

Type II DM characterized by declining beta cell function, insulin resistance and an attenuated incretin effect.

Patients with type two diabetes have increased mortality, and 80% of the deaths caused by cardiovascular complications, often myocardial infarctions.

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that stimulates release following oral intake of glucose.

The effects of incretin hormones are diminished in patients with type II diabetes.

GLP-1 function is retained in type II diabetes and administration of GLP-one receptor agonists can restore the incretin effect in these patients.

In type II diabetes pre-existing insulin resistance and progressive insulin deficiency require higher doses of insulin and gradual upward titration of doses.

During the transition from normoglycemia to type two diabetes women put on more weight and accumulate a higher cardiometabolic risk burden, with a greater deterioration of endothelial function, inflammation, and hypercoagulable state than do male counterparts.

Diabetic ketoacidosis is less common in type II diabetes as insulin deficiency is relative rather than absolute as is present in type I diabetes.

In type II DM circulating endogenous insulin is sufficient to prevent ketoacidosis, but inadequate to prevent hyperglycemia in the face of increased insulin resistance.

Type II diabetes associated with strong genetic influence as monozygotic twins over the age of 40 years have a concordance of over 70% within one year whenever one twin develops the diagnosis.

Other types of diabetes include genetic defects in beta cell function, genetic defects in insulin action, diseases of the exocrine pancreas, such as cystic fibrosis, and drug-induced or chemical induced diabetes, and gestational diabetes mellitus.

Some patients cannot be clearly classified as type I or type II diabetes.

Clinical presentation of type I and type II diabetes varies considerably.

Participating in leisure-time running is associated with a lower risk of the development of type two diabetes in adults.

Type 2 caused by peripheral resistance to insulin action and inadequate secretory response by the pancreatic beta cells.

In type 2 DM age, and amyloid fibrils in islets and chronic elevation of insulin play roles in beta cell failure.

Age of onset of Type II DM is falling.

Type 2 diabetes associated with a reduced first-phase insulin secretion during meals, resulting in hyperglycemia and a 35% decrease in hepatic glycogen storage (Kerren R).

Type II diabetes associated with a 55% increase in nocturnal hepatic gluconeogenesis, resulting in excessive glucose production and fasting hyperglycemia.

Type II diabetes associated commonly with metabolic abnormalities including hypertension, dyslipidemia, inflammation, hyper coagulation, and endothelial cell dysfunction.

Oral glucose lowering agents are the mainstay of diabetes management, but many patients do not achieve adequate glycemic control with oral medications alone.

Triglyceride/HDL ratio of >3 is a risk factor for insulin resistance.

Type two diabetes doubles the risk of major cardiovascular complications in patients with and without established cardiovascular disease.

Majority of patients with diabetes die of cardiovascular diseases.

Diagnosis of diabetes in a person at age 55 results in a reduction in lifespan of five years (Vilbergsson S et al ).

Early in the course of type II diabetes pancreatic hyperplasia of B cells occurs and is associated with fasting a hyperinsulinism, and exaggerated insulin and pro-insulin response to glucose.

Type II diabetes associated with chronic hyperglycemia, although resistance to some actions of insulin and inadequate secretion of insulin are other critical abnormalities.

Overlap between type II diabetes and cancer has been explained by high levels of circulating insulin and insulin like growth factor 1, both of which are growth factors, that characterize insulin resistance states such as type II diabetes.

Among patients who is long-standing type 2diabetes blood pressure lowering treatment attenuated attenuates but significant long-term benefits with respect to death from any causes or cardiovascular causes, whereas intensive glucose control for an average of five years does not provide any long-term benefits with respect to give to a major macrovascular disease.

A number of studies have shown that despite more aggressive glucose control there is no benefit in terms of major cardiac events or most of the microvascular endpoints.

In type II diabetes insulin resistance is typically present years before diagnosis, with decreased stimulation of glucose transport in muscle and adipose tissue and associated with inadequate suppression of glucose production in the liver in response to insulin.

In type II diabetes amyloid deposition in the islet cells may contribute to impaired B cell function.

18 different genetic loci associated with increased risk of type II diabetes mellitus.

Genetic abnormalities in type II DM primary related to beta cell failure.

TCF7L2 gene loci has the largest risk effect for diabetes Type II and codes for a transcription factor involved in the WNT signaling pathway required for pancreatic development.

Other genetic loci associated with type II DM include: CDLAL1, SLC30a8, HHEX-IDE, CDKN2A/B, KCNJ11, and IGF2 by affecting insulin secretion.

PPARG locus is associated with insulin resistance in diabetes type II.

As the majority of patients with type II diabetes are obese, exercise and diet may improve the disease and result in clinical remission in some patients.

Exercise volumes exceeding 150 minutes of exercise per week induces superior improvements in hemoglobin A1 C levels.

Exercise is associated with the decreased need for glucose lowering medications in a dose dependent manner.

The sex hormones of the body, which are believed to play a part in type 2 diabetes development are regulated by a protein known as SHBG (sex hormone-binding globulin).

SHBG plasma levels are increased by coffee consumption.

Research has shown an inverse association between type 2 diabetes risk and coffee consumption: Women consuming a minimum of 4 cups of coffee per day have a 50% less risk of developing diabetes compared to non-coffee drinkers.

Blood levels of SHBG do have an impact on genetic susceptibility to type 2 diabetes development.

Despite lifestyle changes and medications to improve glycemia and control cardiovascular risk, up to 90% of patients with type Ii diabetes achieve treatment goals to reduce long-term risk of complications (Wong K et al).

Olny an estimated 21% of adults with type two diabetes achieve the three risk factor control goals including: individualized hemoglobin A-1 C targets, blood pressure less than 130/80 mmHg, and a low density lipoprotein cholesterol level less than 100 mg/dL.

Laparoscopic gastric banding, Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and duodenal switch or biliopancreatic diversion produce more weight loss and better glycemic control than typical medical therapy in type two diabetics.

ADA recommends a diet rich in fiber, whole grains, legumes, less than 7% satiated fat, reduced trans fats, limited calories, and foods with high glycemic index.

Exercise has additive effects when combined with caloric restriction for glycemic control, and at least 150 minutes

A meta-analysis demonstrated a 38% reduction in all cause mortality in patients with type II DM (Sluik D et al).

Exercise decreases basal insulin levels, increases insulin sensitivity, and decreases glycated hemoglobin levels.

The Look AHEAD (Action for Health for Diabetes), a large randomized controlled trial of intensive lifestyle intervention among adults with type II diabetes: involved 4503 adults with body mass index of 25 or higher and type II diabetes randomly assigned intensive lifestyle intervention.

In the above study intensive lifestyle intervention may be associated with the partial diabetes remission in patients with type II diabetes, particularly those diabetes is of short duration, who have a lower hemoglobin A-1 C level, and do not yet require insulin therapy (Gregg EW et al).

In the above study complete remission associated with intensive lifestyle intervention, when defined by glucose normalization without need for drugs, is a rare event.

In the ADVANCED-ON collaborative group study among patients with long-standing type two diabetes, blood pressure lowering treatment for an average of 4.5 years resulted in the attenuated but significant long-term benefits with respect to death from any cause and from cardiovascular causes, whereas intensive glucose control for an average of five years did not provide any long-term benefits with respect to death or major macrovascular events.

Partial remissions defined as a transition to prediabetic or normal glucose levels without drug treatment is an attainable goal for some patients with type II diabetes, and as many as 11.5% of participants had partial or complete remission within the first year of intervention and 7% in a partial complete remission after four years.

Medical care encounters every two weeks are associated with the fastest achievement of hemoglobin A-1 C., blood pressure and low density lipoprotein-cholesterol targets for patients with diabetes (Morrison F et al).

Type II diabetes eventually is associated with progressive beta cell insufficiency in 90% of patients as lifestyle changes and oral drug therapy are inadequate and patients require exogenous insulin supplementation to keep the hemoglobin A-1 C at the target range of 7%.

The American College of physicians now recommends treating to hemoglobin A-1 C levels of 8% percent rather than 7%, balancing outcomes and adverse events in type two diabetes.

The long-term complications are the same for type 1 and type 2 diabetes.

Type 2 affects nearly 8% of U.S. adults.

Estimated that 194 million people had diabetes worldwide in 2003.

800,000 persons develop diabetes each year in the U.S., with 54,000 deaths.

Leading cause of end-stage renal disease, adult blindness, and lower extremity amputations in the U.S.

The presence of diabetes more than doubles the risk of having a heart attack or stroke.

Some of the risk for increased ischemic adverse events and death in diabetes may be related to platelet hyperactivity and altered platelet receptor and intracellular signaling pathways, including an up regulation of the P2Y12 pathway.

Patients with diabetes often have persistently high platelet reactivity in the presence of clopidogrel therapy.

The prevalence of chronic renal disease in diabetes is 40%, and diabetes is the primary cause of kidney failure in 45% of patients receiving dialysis.

Targeting a hemoglobin A1c lower than 7% slows progression of diabetic kidney disease, including microalbuminuria and overt nephropathy.

Hemoglobin A1c levels higher than 9% in CKD is associated with a markedly worse clinical outcome in diabetics with excess mortality (Shurraw S et al).

Hemoglobin A1c levels within 6.5% in CKD is associated with excess mortality in diabetic patients (Shurraw S et al).

Each 1% decrease in A1C is associated with a 21% decrease in the risk of any adverse clinical outcome related to diabetes, including myocardial infarction, stroke, peripheral vascular disease, and microvascular complications.

Diagnosis of type II DM based on hemoglobin A!C of 6.5 5 or more, fasting plasma glucose of 126 mg/dL or a 2 hour plasma glucose level 200 mg/dL or more during an oral glucose tolerance test.

A random plasma glucose of 200 mg/dL confirms diagnosis of type II DM.

Lifetime risk for individuals born in 2000 is 1 in 3 for males and 2 in 5 for females, with risk 2-5 times higher for African-Americans, Hispanic and Native populations compared to whites.

Prevalence of type 2 diabetes in persons older than 20 years of age 14.7% in the African American community, nearly 50% higher than the 10.7% population averge in the U.S. (Centers for Dsease Control and Prevention).

Estimated that 194 million people had diabetes worldwide in 2003.

Increase type 2 diabetes in Asia has occurred in a much shorter time, in younger patients and in individuals with lower BMI than other worldwide populations.

Obesity could be directly responsible for up to 50% of all new cases of type 2 diabetes.

Asian population has a higher proportion of body fat and prominent abdominal obesity compared to individuals of European origin with similar BMI values, indicating that Asians have a higher predisposition to insulin resistance at a lesser degree of obesity than people of European descent.

More than 75-80% of deaths in people with diabetes is due to cardiovascular disease.

Mortality form other diseases, especially cardiovascular disease is increased in persons with diabetes.

Considered a coronary artery disease equivalent indicating adults with this disease have similar risks of dying from complication of coronary artery disease as to patients with established coronary artery disease.

Cardiovascular mortality risk increases continuously with blood glucose concentration.

By lifestyle changes, controlling blood pressure and lipids and with antiplatelet therapy the development, progression and complications of type 2 diabetes can be reduced.

Type 2 diabetic have a higher fracture rate, which is a paradoxical finding chance it is associated with a higher BMD.

Men with type 2 diabetes have a higher risk of hip and non?vertebral fractures than non?diabetic men.

While glucose control may reduce micro vascular complications, blood pressure control has a greater effect.

Type I form of the disease is associated with progressive reduction in the plasma catecholamine response to hypoglycemia.

Type 1 T cell mediated autoimmune origin with loss of insulin secreting beta cells.

Selective immunologically mediated destruction of beta cells in the pancreas islets of Langerhans with consequent insulin deficiency.

Prediposing factor for pancreatic cancer.

Anti-diabetic therapy modulates the risk of pancreatic cancer:patients treated with insulin or insulin secreatogogues are at higher risk, while those treated with metformin have significantly lower risk.

Metformin, compared with lifestyle modification alone, is associated with a 39% reduction in myocardial infarction and a 36% reduction in all-cause mortality in diabetes,

Autoimmune destruction of beta cells in type I diabetes begins before the onset of hyperglycemia and measurement of C- peptide responses at the time of diagnosis demonstrates that some beta cell function at this stage is retained.

Residual beta cell function in type I diabetes is associated with reductions of severe hypoglycemic episodes and its complications (The Diabetes Control and Complications Trial Research Group).

Patients with mild Type I diabetes may initially have enough beta cell function to prevent acidosis, but later in life insulin dependence will result as the beta cell function diminishes.

Mild type I DM may make up 15% of diabetes patients, known as latent autoimmune diabetes of adulthood.

Type I diabetes is more common in Scandinavian countries and becomes less frequent closer to the equator.

The incidence of type I diabetes increases for populations that emigrate to the northern hemisphere.

Fewer than 10% of patients with type I DM have no evidence for pancreatic B cell autoimmunity explaining absent insulin and ketoacidosis-this type of diabetes is known as idiopathic type I diabetes or type IB diabetes.

Idiopathic type I diabetes is most commonly seen in individuals of Asian or African origin.

Average life expectancy of a person who has diabetes is 15 years less than a person who does not have the disease.

Average healthcare expenditure per year for a diabetic is 2.4 times the amount of money spent on a patient without diabetes.

Estimated to affect more than 6.5% of the population of the U.S.

Prevalence of diabetes among people aged 65-74 years was 16.7% vs 1.4% in people younger than 45 years.

Three ways to diagnose diabetes are recommended and they include fasting plasma glucose levels, 75 g oral glucose tolerance test and an elevated A1 C. hemoglobin level.

Fasting glucose level of 126 mg/dl or more is a positive result.

Individuals with a fasting glucose greater than 110 mg/d/L but less than 126 mg/dL, or oral glucose tolerance test results greater than 140 mg/dL but less than 200 are considered to have impaired glucose tolerance.

5-10% of patients with impaired glucose tolerance develop diabetes each year.

75 gm glucose load international standard for the diagnosis of diabetes.

Random blood glucose value of 160 mg/dl or above is abnormal.

Greater risk for infection-related mortality.

Increases the risk of developing tuberculosis by three fold.

Two-hour glucose level is better than fasting glucose level alone at identifying older adults at increased risk of major incident cardiovascular events.

Impaired fasting glucose refers to blood sugars of 100 mg per deciliter 225 mg per deciliter.

Impaired glucose tolerance refers to two hour plasma glucose of 140 mg per deciliter to 199 mg per deciliter.

Impaired fasting glucose and impaired glucose tolerance are referred to as pre- diabetes.

By the time the diagnosis is made 70-90% have metabolic syndrome.

Decreased glucose utilization in cells of satiety areas of the hypothalamus is associated with hyperphagia.

Claims more lives than breast cancer and AIDS combined.

Cancer and diabetes are often diagnosed simultaneously.

in patients with  Cancer, Diabetes is associated with higher rates of complications, higher risk for hospitalization, increased mortality, increased psychological distress, decreased quality of life. and diabetes is a common cause of non-cancer mortality in patients with cancer.

Female patients with diabetes have 3 times the coronary heart disease mortality rate of age and sex matched controls.

At the time of diagnosis 29% have retinopathy, 10% to 37% have proteinuria, 9% have neuropathy, 22% have abnormal heart findings, 19% have coronary artery disease, 10% have peripheral vascular disease, 61% have hypertension and 49% have hypercholesterolemia.

Almost 21% of patients with newly diagnosed diabetes have retinopathy, indicating that the disease may be active for seven years before the diagnosis (Harris MI).

Every patient should have an annual eye examination.

High levels of plasma homocysteine associated with risk of developing diabetic neuropathy and retinopathy.

Arsenic exposure linked to the development of type 2 diabetes (Navas-Acien).

3.6 fold increase in the odds of developing diabetes in patients with the highest total urinary arsenic levels as compared to those with the lowest urinary arsenic concentrations.

All diabetic patients should be screened at least annually for diabetic neuropathy.

The kidney plays a major role in glucose homeostasis by gluconeogenesis and glomerular filtration absorption of glucose in the proximal convoluted tubules.

The glomeruli of the normal adult kidney filters 180 g of glucose daily.

Glucose reabsorption from the tubules is virtually complete with less than 1% being excreted in the urine.

The reabsorption of glucose from kidney tubules is a multistep process and once filtered into the tubule must be transported through the tubular epithelial cells and then across the basolateral membrane into tubular capillaries.

When tubular glucose load is approximately 120 mg/minute or less, no glucose is lost in the urine.

When tubular glucose load exceeds 220 mg/minute, the glucose threshold, glucose begins to appear in the urine.

Glycosuria generally does not occur until the blood glucose concentration exceeds 180 mg per deciliter.

Patients with symptoms of hyperglycemia and/or persistent blood sugar levels greater than 300 mg/dl should initially be started on insulin.

A persistently high blood sugar level is toxic to the beta cells and may contribute to peripheral insulin resistance.

The association of a non-alcoholic fatty liver disease with concurrent diabetes increases mortality ( AdamsLA et al).

Chronic liver disease associated with glucose intolerance and diabetes.

Glucose intolerance is seen in up to 80% of patients with chronic liver disease and frank diabetes is noted to be present in up to 30-60% of such patients.

HA1C level are falsely low in diabetics with liver disease limiting the usefulness of this monitoring tool.

Chronic hepatitis C is associated with insulin resistance causing impaired glucose tolerance, as a result of fat accumulation in liver cells, increased insulin resistance secondary to increased tumor necrosis factor-alpha and damage to beta cells by the virus (Antonelli A et al).

Hemochromatosis associated with odds ratio for diabetes as high as 5.4 compared to control subjects.

In a study involving 4038 patients with diabetes, disease, and anemia were randomly assigned to darbepoetin to achieve a hemoglobin of approximately 13 g per deciliter compared to placebo and darbepoetin rescue when the hemoglobin was less than 9 g per deciliter: the use of darbepoetin for diabetic patients with chronic kidney disease and moderate anemia, who were not undergoing dialysis did not reduce death, or cardiovascular events, or renal events and was associated with an increased risk of stroke(Trial to Reduce Cardiovascular Events with Aranesp Therapy [TREAT}.

Chronic kidney disease with diabetes is associated with chronic inflammation and oxidative stress resulting in glomerular dysfunction, mesangial cell contraction, mesangial expansion, and decline in kidney function.

Approximate initial dose of bedtime NPH insulin can be calculated as 25% of patient weight in kgs.

Dyslipidemia abnormalities include elevated very-low-density lipoprotein (VLDL) triglycerides, low-density lipoprotein (LDL) cholesterol particles and decreased levels of high-density lipoprotein (HDL) cholesterol.

All elements of diabetic dyslipidemia are independently atherogenic.

Lipid management can reduce major coronary heart disease events, deaths, non fatal myocardial infarctions, or myocardial revascularization procedures.

Primary goal of lipid related therapy is LDL-C level less than 100 mg/dL for patients with type 2 diabetes.

Collaborative Atorvastatin Diabetes Study (CARDS) assesses effectiveness of Lipitor versus placebo in the primary prevention of cardiovascular disease inpatients with type 2 diabetes: resulted in a 37% reduction in the incidence of major cardiovascular events, with 36% reduction in acute coronary events, and a 48% reduction in stroke and 31% reduction in coronary revascularization events, 27% reduction in total mortality and a 32% reduction in the rate of any acute cardiovascular event.

The Treating to New Targets (TNT) study randomized, double blind parallel group study assessed lowering LDL-C <100 mg/dL in diabetic men and women with coronary heart disease and mean LDL-C <130 mg/dL aged 35-75 years to receive Lipitor 80 mg/day vs. Lipitor 10 mg/day: the 80 mg/day dose associated with a mean reduction of LDL-C level of 77 mg/dL and a 22% relative risk reduction in cardiovascular events compared with a mean level of LDL-C of 101 mg/dL with the lower dose.

Complications of atherosclerosis are responsible for about 80% of deaths in diabetic patients.

Higher than optimal blood glucose levels accounts for 21% of ischemic heart disease and 13% of stroke mortality.

Higher than optimal blood glucose levels in the top five determinants of world mortality accounting for 3.16 million deaths a year.

Elevated levels of CRP and IL-6 predict the development of type 2 diabetes.

Combined diet and physical activity interventions have been found to be successful in reducing the rate of conversion from impaired glucose tolerance to type 2 diabetes.

Eating whole fruits particularly apples, blueberries, and grapes are significantly associated with a lower risk of type two diabetes by 23%.

Consumption of fruit juices link to higher risk of type two diabetes, increasing risk by 21%.

A plasma glucose of 200 mg/dl or more 2 hours after ingestion of 75 gm of glucose is abnormal.

Women with diabetes have lower HDL level.

Associated with a greater risk for breast cancer, advanced stage breast cancer and decreased 5 year survival.

Typically the diabetic lipid profile consists of hypertriglyceridemia, raised levels of very low-density lipoprotein (VLDL), and reduced levels of high-density lipoprotein (HDL).

There is a gradient of mortality associated with abnormal glucose tolerance ranging from 40% greater risk in adults with impaired glucose tolerance to a 110% greater risk in adults with clinically evident diabetes.

Up to 50% of patients with diabetes diagnosed by oral glucose tolerance tests would be missed by current fasting blood glucose criteria.

Beta cell function progressively deteriorates with increasing duration of type II diabetes, partly because of beta-cell apoptosis.

Interleukin-10 is a proinflammatory cytokine implicated in beta cell destruction leading to type I diabetes by inhibiting the function and promoting apoptosis of beta cells.

Inflammation likely accelerates development of diabetes mellitus.

Inflammation may cause insulin resistance.

Type 2 diabetes is also known as an inflammatory condition, associated with increased plasma IL-6 and TNF-? concentrations 40 and enhanced activity of the transcription factor nuclear factor B, a master regulator of inflammatory responses.

TNF inhibitors used in inflammatory diseases improve insulin resistance.

IL-1 receptor antagonists can reduce hemoglobin A!C in patients with type II diabetes.

Hydroxychloroquine in patients with rheumatoid arthritis reduced the risk of incident diabetes (Wasco MC et al).

Beta cells producing Interleukin-10 have been seen in pancreatic secretions in patients with type 2 diabetes.

Suggested that intra-islet production of inflammatory mediators has a role in the causation of type 2 diabetes.

Interleukin-1 receptor antagonist a competitive inhibitor of Interleukin-1 binding to the type I receptor can protect human beta cells fro glucose induced functional impairment and apoptosis.

The expression of Interleukin-1 receptor antagonist is decreased in beta cells in patients with diabetes type 2.

30-50% of patients with longstanding diabetes have delayed gastric emptying (gastroparesis).

Diabetes is associated with gastric emptying abnormalities that include transient slow gastric emptying, transient fast gastric emptying, persistent slow or delayed gastric emptying, and persistent fast gastric emptying.

 

 

Transient changes in gastric emptying do not require treatment.

 

 

Delayed gastric emptying and rapid gastric emptying are associated with abdominal symptoms and they can cause severe illness.

 

 

Delayed gastric emptying may cause  difficulty in glucose control in patients receiving insulin. 

 

 

Rapid gastric emptying plays in important role in the genesis  and progression of type two diabetes mellitus. 

 

 

Treatment of rapid gastric emptying is an important target for the management of post prandial hyperglycemia.

 

Diabetes leading cause of blindness ages 20-74 years.

Depression associated with a 60% increase in risk of type II diabetes (Mezuk B et al).

Diabetes increases the risk of depression.Depression in diabetics associated with increased risk of dementia.

The risk ratio of the association between diabetes and dementia is between 1.43 and 1.62.

The younger the age of diabetes onset the higher risk for subsequent development of dementia.

Most common cause of end-stage renal disease, accounting for 40% of cases.

High dose statin therapy improves cardiovascular outcomes in diabetic patients with mild to moderate chronic renal disease.

High dose atorvastatin reduces the relative risk of major cardiovascular events by 35% in diabetic patients with chronic renal insufficiency but only 10% in those with diabetes and normal kidney function.

Tight control in type 2 diabetes reduces risk of any diabetic related end point, death related to diabetes, fatal and nonfatal strokes and heart failure.

Heart failure and type two diabetes are linked.

When heart failure develops in patients with type two diabetes it is complicated by markedly higher rates of mortality.

Diabetes mellitus is associated with increased risk of heart failure with reduced ejection fraction, heart failure with preserved ejection fraction, and sub clinical left ventricular dysfunction.

The prevalence of heart failure with reduced ejection fraction is 40% or less versus heart failure with ejection fraction is greater than 40% in patients with diabetes.

Type II diabetes-protein ingestion results in a small decrease in postprandial glucose concentrations.

Duration and level of elevated sugar are important determinants of microvascular complications of diabetes, including neuropathy.

HbA1c levels maintained below 7.2% reduces the incidence of nephropathy, retinopathy, and neuropathy.

Achieving an HbA1c of 7% effectively prevent progression the diabetic retinopathy, neuropathy or nephropathy but it is at that level that cardiovascular benefits of improved glycemic control begins.

A 14% reduction in myocardial infarction is linked to every 1% reduction in HbA1c level.

For frail older patients the recommended target hemoglobin A-1 C recommendation is 8-9%.

Most frail elderly patients greater than 65 years of age have a life expectancy of less than eight years making diabetic vascular outcomes less important.

For frail elderly patients tight glycemic control can lead to dietary restrictions, frequent finger sticks, insulin management, polypharmacy an increased risk of hypoglycemia with little chance that they will survive long enough to benefit from lower rates of vascular complications.

And increased fasting plasma glucose level is associated with a relatively higher risk of in-hospital mortality in men but not in women (Yang SW et al).

For otherwise healthy younger adults the primary goal of glycemic control is focused on decreasing vascular problems, such as stroke and retinopathy: these complications result from decades of poor glycemic control.

Tight glycemic control for approximately 8 years is necessary before decrease in vascular outcomes occur (Brown AF et al).

There is a U. shaped relationship between fasting plasma glucose levels and in-hospital and three-year mortality for acute myocardial infarction (Yang SW et al).

For every 1% HbA1c above 5% there is an increase of 27% in cardiac events.

There is a 40% increases in cardiac events for the diabetic for each 1% increase in HbA1c above 1%.

Optimal control is defined as a HbA1c <6.5%.

All diabetic patients above the age of 12 should be screened annually for microalbuminuria.

Intensively managed type I patients gain and average 15.3 years free of complications and 5.3 years of life expectancy in comparison with less tightly controlled patients.

Lifestyle modification including weight reduction and increased physical activity can reduce the prevalence of type 2 diabetes by as much as 58% (Knowler).

The average HbA1c level among all diabetics in the U.S. remains at about 8.7%.

Small size at term birth and during infancy associated with increased risk of impaired glucose metabolism and cardiovascular disease later in life.

Neonatal diabetes refers to onset of disease with mild to severe hyperglycemia within the first months of life.

Neonatal diabetes may require lifelong treatment or may be transient remitting early with possible relapse in adolescence.

Heterozygous mutations in KCNJ11 gene encodes the Kir6.2 subunit of the KATP channel causes diabetes in the neonatal period or early infancy.

30-58% of cases of permanent diabetes in patients under six months of age have KCNJ11 gene mutations.

Type 1 increased disease worldwide with a 54% increase in the U.S. in the past 7 years.

KCNJ11 mutations may be associated with transient neonatal diabetes which may be accompanied by neurological abnormalities.

Type I diabetes in children under the age of 18 cumulative survival 98% at 10 years and 79.6% at 30 years.

Type II diabetes incidence increasing worldwide.

Type 2 development can be correlated with visceral fat.

Type 2 strongly associated with below normal levels of testosterone (hypogonadism), with 40% of men with type 2 diabetes between the ages of 40-49 years and nearly 55% of men in their 70’2 with hypogonadal levels.

The low levels of testosterone in men with type 2 diabetes may be relate to high prevalence of erectile dysfunction among such men, estimated to be between 35-75%.

Type 2 associated with adipocytokines (TNF-alpha, plasminogen activator inhibitor type 1, and IL-6) released from adipose tissue and which impair insulin signaling, fibrinolysis and endothelial processes.

Type 2 associated with reduced circulating levels of adiponectin which is associated with increased insulin resistance and obesity.

Obesity is the most important environmental factor causing insulin resistance in type II diabetes and is found in 60 to 70% of North Americans, Europeans and Africans, 100% of Pima Indians, but only 30% of Chinese and Japanese.

Visceral accumulation of fat in the omentum and mesentery correlates with insulin resistance and type II diabetes, while subcutaneous abdominal fat has a lesser association.

Alpha2A-adrenergic receptor gene (ADRA2A) polymorphism associated with reduced ability of pancreatic beta cells to release insulin.

Beta cells of persons carrying ADRA2A allele have too many alpha2a-adrenergic receptors impairing the dockimng of insulin granules at the plasma membrane, resulting in impaired release of insulin containing vesicles in response to a rising blood sugar level.

Risk of diabetes increases continuously with increasing body mass index and the relationship between obesity and diabetes is also age-dependent.

Type 2 risk appears to be polygenic involving a number of genetic variants, each with a modest effect on the risk of the development of the disease.

Adults that have normal weight at the time of diagnosis of type 2 diabetes have a higher mortality than adults who are overweight or obese.

Type II-at the time of diagnosis about 50% of endogenous beta cell function is retained.

Research shows that managing stress through meditation and exercise can also help to lower blood sugar levels.

Sleep helps a person reduce the amount of sugar in their blood.

Getting adequate sleep each night is an excellent way to help keep blood sugar levels at a normal level.

Blood sugar levels tend to surge in the early morning hours.

Lack of sleep can have a similar effect to insulin resistance, meaning that a person’s blood sugar level could spike significantly from lack of sleep.

Type 2 characterized by insulin resistance associated with increased hepatic glucose production and reduced glucose clearance with impaired beta cell insulin secretion.

Type 2 associated with insulin secretory activity of beta cells which is proportional to the dose of glucose which is controlled by glucokinase enzyme kinetics that converts glucose into glucose 6 phosphate.

9 classes of oral anti diabetic medications exist.

Agents that improve insulin sensitivity include: metformin, and thiazolidinediones pioglitazone and rosiglitazone.

Metformin stimulates AMP-activated protein kinase and reduces hepatic glucose production.

Metformin recommended as initial treatment for type 2 diabetes, in the absence of specific contraindications.

If diabetes is not well controlled with maximum tolerated doses of metformin other medications should be added.

Thiazolidinediones are peroxisome proliferator-activated receptor gamma activators that enhance insulin sensitivity in peripheral tissues and reduce hepatic glucose production.

The American Diabetes Association recommend the addition of a sulfonylurea or insulin when monotherapy with metformin is insufficient care.

The bile acid sequestrate colesevelam reduces hepatic glucose production and increases incretin levels to improve diabetes.

Bromocriptine the dopamine agonist activates D2 dopamine receptors and increases insulin sensitivity to improve diabetes.

The thiazolidinedione pioglitazone may be added to metformin when hypoglycemia is especially undesirable.

Randomized, double blind, placebo controlled study of sitagliptin and metformin in patients aged 18-78 years with type 2 diabetes-randomization to 6 groups with monotherapy, combination therapy or placebo: combination of agents resulted in statistical improvement in achieving A1C level goals and changes in fasting glucose levels (Goldstein).

Glucose must be transported across the beta cell membrane into the cytoplasm, (mediated by the glucose transporter 2 (GLT-2)), before glucokinase can act on glucose.

Type II-after 6 years only 25% of beta cell function remains.

Type II diabetes is estimated to be present prior to clinical diagnosis by 10-12 years.

Type II diabetes can be prevented by changes in lifestyle of high-risk subjects.

Type II diabetes-despite lifestyle and pharmacologic treatment, glucose levels increase over time as a consequence of declining beta cell function.

Type 2-only oral agent that can decelerate decline in beta cell function, may preserve and even increase beta cell mass is a thiazolidinedione, which is the reason this type of drug should be used as the first drug for treatment.

Type 2-in most situations a thiazolidinedione should be combined with metformin in treatment.

Metformin contraindicated in elderly patients with abnormal creatinine level, or in patients with renal or hepatic difficulties or in patients on treatment for congestive heart failure, and in such cases a combination of sulfonylurea and a thiazolidinedione should be used.

If metformin mono therapy cannot be utilized other oral agents such as a sulfonylurea, DPP-IV inhibitor or a GLP-1 receptor agonist can be given.

Combinations of agents include metformin plus another oral agent, or longer acting Insulin may be used,and there is no strong evidence supporting one particular 2nd agent over another.

Patients with chronically high levels of hemoglobin A-1c of approximately 9% are unlikely to have adequate glycemic control with metformin alone.

In patients with blood glucose levels of or greater than 300 mg/dL (greater than 10% hemoglobin A-1 C) initial diabetic therapy with insulin should be considered.

Glyburide is the most commonly used secretagogue and should be avoided because of the high incidence of hypoglycemia.

Glyburide plus metformin compared to metformin plus rosiglitazone (Avandia) revealed a better HbA1c lowering with glyburide plus metformin, although associated with greater frequency and severity of hypoglycemia with hypoglycemic episodes of 38.3% vs 1.3%, respectively.

Type II diabetes-weight loss is the main treatment in overweight individuals with type 2 diabetes.

In obese patients with type 2 DM 12 months of medical therapy plus bariatric surgery achieves greater glycemic control in significantly more patients than does medical management alone (Schauer PR et al).

In the above study of obese patients with poorly controlled diabetes who underwent either gastrric bypass orsleeve gastrectomy combined with medical therapy were significantly more likely to achieve hemoglobin A-1 C. levels of 6% or less one year after randomization then were patients receiving medical therapy alone.

Fewer than 50% with moderate to severe type 2 DM achieve and maintain glycemic control.

Hyperglycemia in type II diabetes leads to accumulation of hexosamines which impairs insulin action.

Type II diabetes-weight gain is a major complication of treatment with sulphonylureas, insulin or thiazolidinediones.

Type 2-associated with deficiency in incretin glucagon-like peptide 1 (GLP-1).

In type II diabetes abnormal postprandial suppression of glucagon secretion occurs.

Beta-cell failure is mediated by genetics, and exposure to chronically elevated blood sugars and free fatty acids.

Type 2-adding exenatide injection to oral therapy is an alternative to insulin and can decrease HbA1c by as much as 1%.

Thiazolidinediones associated with weight gain but when added to metformin weight gain is minimal, stable or even may be associated with weight loss.

Insulin initiation is usually with a single dose of basal long acting insulin preferably at bedtime and starting with approximately 10 units and increasing like to-3 units every several days will reduce the hemoglobin A1 C levels to 1.5-2% or more.

If hyperglycemia is not controlled rapid acting insulin can be added at the largest meal.

Treatment with premixed biphasic insulin preparations that are usually given before breakfast and dinner, or basal insulin plus rapid acting insulin therapy before a meal is also a consideration.

An estimated 65% of patients will have an myocardial infarction or stroke, four times the rate of non diabetics.

Body fatness is perhaps the most notable modifiable risk factor for the development of type II diabetes.

Hypertension in diabetes is a risk factor for microvascular complications of the retina and kidney.

Hypertension Optimal Treatment (HOT) trial suggested reduced cardiovascular outcomes for diabetic patients assigned to diastolic treatment goal of less than 80 mm Hg compared to treatment with higher goals (Hannson L).

United Kingdom Prospective Diabetes Study group data indicated tight control of blood pressure reduced macrovascular and microvascular outcomes.

In the above study longer-term follow-up indicated a reduced risk of cardiovascular disease events 10 years after the end of the trial among patients who were initially randomly assigned to intensive glycemic management, as compared with conventional therapy with average glycated hemoglobin level 7% versus 7.9%, respectively.

Trials involving older individuals with established type II diabetes and history of or risk factors for cardiovascular disease showed no reduction in total mortality or cardiovascular disease related mortality associated with intensive lowering of glucose levels, as compared with standard glycemic control.

Intensive glycemic control is associated with higher rates of hypoglycemia and weight gain in type II diabetics.

In management of type II diabetes microvascular benefits from intensive glycemic control must be balanced against risks.

Tight control of systolic blood pressure among patients with diabetes and coronary artery disease is not associated with improved cardiovascular outcomes compared with usual control (Cooper-DeHoff, RM).

In the above study during 16893 patient-years of follow-up the same degree of cardiovascular outcomes was noted among the tight controlled group and the usual treatment control group (Cooper-DeHoff, RM).

Decreasing systolic blood pressure to lower than 130 mm Hg in patients with diabetes and coronary artery disease is not associated with further reduction in morbidity beyond that associated with systolic blood pressure lower than 140 mm Hg, and is associated with an increase in all-cause mortality (Cooper-DeHoff, RM).

Treatment of hyperglycemia alone does not prevent macrovascular disease in patients with type 2 diabetes.

Among patients with DM, ACE inhibitors fared better than placebo in reducing creatinine doubling, and beta-blockers were associated with an increased risk of death.

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial indicated no significant decrease in cardiovascular events with intensive glucose control.

ACCORD trial ended early, after 3.5 years because of significant increase in deaths in the intensive therapy group.

ACCORD Lipid trial: randomly assigned 5518 patients with type 2 diabetes with simvastatin with fenofibrate vs placebo-mean follow-up 4.7 years, the combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke as compared to simvastatin alone.

ACCORD trial randomly assigned patients with type 2 diabetes and cardiovascular disease received intensive therapy, Hgb A1C target <6.0 or standard therapy Hgb A1C 7-7.9-follow up after termination of the study at 5 years revealed reduced nonfatal myocardial infarctions but increased 5 year mortality (ACCORD Study Group).

In the ACCORD trial the patients had diabetes for a median of ten years, and a Hgb A1C level of at least 7.5%, and high risk for cardiovascular disease: intensive treatment did not significantly reduce cardiovascular events and led to more deaths.

ACCORD trial indicated intensive glycemic control increased the risk of death by 22%.

Despite increase use of glucose lowering medications and inhibitors of renin-angiotensin-aldosterone system from 1998-2008 the prevalence of chronic kidney disease in diabetic patients increased.

In the Veterans Affairs Diabetes Trial (VADT) 1791 veterans with type II diabetes were randomized to receive intensive or standard therapy for glucose control: median Hgb A1C was 8.4% in the standard group and 6.9% in the intensive therapy group, no difference in primary outcomes, rate of death, and no difference for microvascular complications. while the rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard therapy group and 24.1% in the intensive therapy group.

Abnormal exercise electrocardiographic results during maximal exercise testing is associated with an increased risk of cardiovascular disease, coronary artery disease in 2854 men with diabetes (Lyerly GW).

Aerobics study showed 12 year cardiovascular and overall mortality approximately 60% lower with moderate to high cardiovascular fitness at baseline compared with those with low baseline fitness (Wei M et al).

Aerobic and resistance training has beneficial effects on glycemic control and insulin sensitivity.

About 15% of persons with diabetes will have an ulcer in their lifetime.

Interruption of the renin-angiotensin system with angiotensin I or II converting enzyme inhibitors slow the progression of renal disease in type I and type II diabetes.

Infants of mothers with diabetes have an increased risk of birth defects.

Type II diabetics have a high risk of miscarriage and congenital malformations, almost twice the risk seen with type I diabetes.

Increases risk of stroke 2-6 times compared to non-diabetics.

Adults with diabetes have a 2-4 fold increased risk of cardiovascular events and a 60% increased risk of early death compared to nondiabetics.

Increased morbidity and mortality among hospitalized individuals with acute illness and diabetes, and in patients with hyperglycemia without known diabetes.

With tight diabetic control in the ICU may decrease morbidity and mortality, but may be associated with higher levels of hypoglycemic episodes.

The presence of renal or hepatic dysfunction is associated with higher likelihood of hypoglycemic episodes.

The liver and kidneys are primarily responsible for gluconeogenesis and glycogenolysis, and also for insulin degradation: dysfunction of these organs will therefore provide less endogenous glucose production, alone were insulin half-life and a higher risk for hypoglycemia.

Pancreoprivic diabetics have greater risk for hypoglycemia episodes since injury or removal of the pancreas decreases both beta cells and alpha cells with secondary glucagon deficiency.

Critically ill patients in ICUs should have oral antidiabetic and subcutaneous insulin discontinued and the use of regular insulin intravenously instituted.

Following autologous nonmyeloblative hematopoietic stem cell transplantation in patients with type I diabetes mellitus a follow-up at 29.8 months C-peptide levels increased significantly and majority of patients achieved insulin independence with good glycemic control (Couri E).

Type I patients that were continuous insulin free after nonmyeloablative hematopoietic transplant increased C-peptide levels occurred up to 24 months after transplantation and wee maintained until at least 24 months (Couri).

Type I patients had increased endogenous insulin production as the main mechanism of euglycemia after nonmyeloablative hematopoietic transplantation.

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.

 

 

Patients  with type 1 diabetes are higher risk for other autoimmune diseases: autoimmune thyroid disease, celiac disease, rheumatoid arthritis, and lupus.

Late microvascular complications are inversely related to C-peptide levels.

Resistance training decreases HbA1c by 0.66% in individuals with type 2 diabetes (Boule NG et al).

Among overweight and obese adults with type II diabetes intensive lifestyle intervention leads to a relative reduction of 40% in the severity of mobility related disability, as compared with diabetes support and education (Look Ahead of Research Group).

In a double-blind study assigned 12,536 patients at high risk for cardiovascular events and impaired fasting glucose, and impaired glucose tolerance, or diabetes to receive 1 g capsules of at least 900 mg of ethyl esters of n-3 fatty acids or placebo daily and to receive either insulin or standard care, the primary outcome was death from cardiovascular causes: daily supplementation with fatty acids did not reduce the rate of cardiovascular events in these patients (The ORIGIN Trial Investigators).

Guidelines for management suggests glycated hemoglobin levels of 7% or less than 6.5%.

In general hemoglobin A-1 C levels should be checked twice yearly.

ADA framework stratifies patients by health status to classes: healthy, complex or very complex with hemoglobin A-1 C goals of less than 7.5%, less than 8%, and less than 8.5%, respectively.

Glycemic control involves nutrition counseling and a diabetic education.

Comparing an insulin pump to a automated bihormonal, bionic pancreas revealed that the latter improved mean glycemic levels, with less frequent hypoglycemic episodes among both adults and adolescents with type I diabetes mellitus (Russell SJ et al).

Guidelines suggest that in patients who have established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure should be treated with a sodium glucose code transporter 2 inhibitor or glucagon-like peptide 1 receptor agonist, irrespective of hemoglobin A-1 C
Exceptions to the above include signs of catabolism such as unintentional weight loss, hemoglobin A-1 C higher than 10% or glucose levels higher than 300 mg/dL in which case insulin should be considered.
When weight gain mitigation is a primary objective the use of SGLT2 inhibitors and GLP-1 receptor agonist is suggested.
Insulin therapy is recommended at or near the end of treatment algorithms for diabetes with previous agents.
By controlling hemoglobin A1c, low density lipoprotein cholesterol, albuminuria, smoking, and blood pressure in type 2 diabetes, the risks of death and myocardial infarction and stroke is similar to patients without type two diabetes.

 

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