Obesity and Diabetes

 Obesity: 

Obesity" specifically refers to an excessive amount of body fat. "Overweight" refers to an excessive amount of body weight that includes muscle, bone, fat, and water. Today, about 65 percent of adults in the United States are overweight or obese. Obesity puts people at increased risk for chronic diseases such as heart disease, type 2 diabetes, high blood pressure, stroke, and some forms of cancer.

 

Body Mass Index:

 

Normally, the production of leptin is to counteract the buildup of fats by at least two differentmechanisms: (1) Stimulating energy production and (2) inhibiting appetite.

Regulation of Energy Balance:

In a biological system, ATP is the major energy carrier The body mass index (BMI) is a tool used to assess overweight and obesity and monitor changes in body weight. It has limitations because it does not measure body fat or muscle directly. BMI is calculated by dividing a person's weight in pounds by height in inches squared and multiplied by 703.

Two people can have the same BMI but different body fat percentages. A bodybuilder with a large muscle mass and low percentage of body fat may have the same BMI as a person who has more body fat. However, a BMI of 30 or higher usually indicates excess body fat.

The BMI table provides a useful guideline to check your BMI. First, find your weight on the bottom of the graph. Go straight up from that point until you come to the line that matches your height. A BMI of 25 to 29.9 indicates a person is overweight. A person with a BMI of 30 or higher is considered obese.

Causes:

Obesity occurs when a person consumes more calories from food than he or she burns. Our bodies need calories to sustain life and be physically active, but to maintain weight we need to balance the energy we eat with the energy we use. When a person eats more calories than he or she burns, the energy balance is tipped toward weight gain and obesity. This imbalance between calories-in and calories-out may differ from one person to another. Genetic and environmental factors may all play a part. At the molecular level, a protein called leptin has been shown to play a central role in obesity . In less than 1% of cases, obesity is caused by a disease, such as Cushing's syndrome, hypothyroidism, or polycystic ovarian disease.

Treatment:

Physical Activity

Physical activity helps you control your weight by using excess calories that would otherwise be stored as fat. Most foods you eat contain calories, and everything you do uses calories. Balancing the calories you eat with the calories you use through physical activity will help you reach and maintain a healthy weight.

Experts recommend at least 30 minutes of moderate-intensity physical activity on most, if not all, days of the week. Physical activity may include structured activities such as walking, running, basketball, or other sports. It may also include daily activities such as household chores, yard work, or walking the dog. Pick a combination of structured and daily activities that fit your schedule.

Diet

For slightly overweight people (BMI 25-30), follow a healthy eating plan which:

• Emphasizes fruits, vegetables, whole grains, and fat-free or low-fat milk and milk products.
• Includes lean meats, poultry, fish, bean, eggs, and nuts.
• Is low in saturated fats, trans fats, cholesterol, salt (sodium), and sugars.

For obese people with BMI greater than 30, a doctor may recommend very low-calorie diet (VLCD) that typically uses commercially prepared formulas to promote rapid weight loss. These formulas, usually liquid shakes or bars, replace all food intake for several weeks or months. VLCD formulas need to contain appropriate levels of vitamins and micronutrients to ensure that patients meet their nutritional requirements. Some physicians also prescribe very low-calorie diets made up almost entirely of lean protein foods, such as fish and chicken. People on a VLCD consume about 800 calories per day or less.

Medications

Appetite suppressants. Most available weight-loss medications approved by the Food and Drug Administration (FDA) are appetite-suppressant medications. These include sibutramine, phentermine, phendimetrazine, and diethylpropion. Appetite-suppressant medications promote weight loss by decreasing appetite or increasing the feeling of being full. These medications make you feel less hungry by increasing one or more brain chemicals that affect mood and appetite. Phentermine and sibutramine are the most commonly prescribed appetite-suppressants in the United States. 

NOTE: Amphetamines are a type of appetite suppressant. However, amphetamines are not recommended for use in the treatment of obesity due to their strong potential for abuse and dependence.

Lipase inhibitors. The drug orlistat reduces the body’s ability to absorb dietary fat by about one-third. It does this by blocking the enzyme lipase, which is responsible for breaking down dietary fat. When fat is not broken down, the body cannot absorb it, so it is eliminated and fewer calories are taken in. In 2007, orlistat was approved for over-the-counter (OTC) sale for adults age 18 and over. This means that the drug may be purchased without a prescription.

Surgery

Severe obesity is a chronic condition that is difficult to treat through diet and exercise alone. Bariatric surgery is an option for people who are severely obese and cannot lose weight by traditional means or who suffer from serious obesity-related health problems. The operation promotes weight loss and reduces the risk of type 2 diabetes by restricting food intake and, in some operations, interrupting the digestive process to prevent the absorption of some calories and nutrients. Recent studies suggest that bariatric surgery may even have a favorable impact on mortality (death) rates in severely obese patients. The best results are achieved when bariatric surgery is followed with healthy eating behaviors and regular physical activity.

Leptin and Obesity:

Obesity is characterized by excessive growth of adipocytes (fat cells), which are the primary site for energy storage. Leptin is a 167 amino acid protein, encoded by the obesity (ob) gene. It is expressed mainly in adipocytes: the more fats in the body, the more leptin molecules are produced. 

. Hydrolysis of ATP to ADP and then to AMP releases energy. ATP can be produced from the oxidation of free fatty acids. In adipocytes, energy is stored in the form of triglycerides (fats). A triglyceride molecule consists of three fatty acid chains and a glycerol. When the body needs energy (e.g., during exercise), some hormones can activate a hormone-sensitive lipase that is present in large quantity at the fat cell membrane. The activated lipase then causes the breakdown of triglycerides, releasing free fatty acids for the production of ATP. This process will reduce fats.

AMP-activated protein kinase (AMPK) is an important energy regulator. This enzyme is activated by rising AMP concentration (which generally is coupled to falling ATP level). Upon activation, AMPK can turn on ATP-producing pathways (such as fatty acid oxidation and glycolysis) and switch off ATP-consuming pathways (such as lipogenesis). Thus, activation of AMPK has the effect of reducing fats.

Adipocytes can release a class of molecules known as adipokines for the regulation of energy homeostasis. This class includes leptin, adiponectin, tumor necrosis factor-α and many others. Both leptin and adiponectin can activate AMPK. In addition, these adipokines are interrelated. For instance, leptin can stimulate adiponectin expression, thereby enhancing the activation of AMPK.

Regulation of Appetite

The appetite is controlled by two types of neurons in the hypothalamus of the brain: NPY/AgRP neurons and POMC/CART neurons. Activation of the NPY/AgRP neurons releases NPY (neuropeptide Y) and AgRP (agouti-related protein), which stimulate appetite. Activation of the POMC/CART neurons releases α-MSH (α-melanocyte-stimulating hormone) and CART (cocaine and amphetamine-regulated transcript), which inhibits appetite. POMC (Pro-opiomelanocortin) is the precursor of α-MSH.

Leptin may circulate through the bloodstream to these neurons and act on its receptors, which relay the signal via the JAK/STAT pathway. In the NPY/AgRP neurons, leptin suppresses the expression of NPY and AgRP, while in the POMC/CART neurons, it enhances the expression of POMC and CART. Therefore, in both sets of neurons, leptin acts to reduce food intake, making the body leaner.

Leptin Resistance

When the normal function of leptin was discovered, researchers thought that leptin might be used to treat obesity. Unfortunately, this is true only for very rare cases caused by defects in leptin or its production. For most obese people, leptin and its production are normal. In fact, since the production of leptin increases with increasing fats, most obese people have high level of leptin, but it does not induce the expected responses. This phenomenon is called leptin resistance. 

Leptin resistance is associated with impairment of leptin transport across the blood-brain-barrier or leptin signaling such as reduced leptin receptor activity or leptin receptor blockade. It has been found that SOCS-3 (suppressor of cytokine signaling 3) and STAT3 phosphorylation are involved .

Bariatric Surgery

Bariatric surgery is used to treat severely obese people. There are four types of operations that are commonly offered in the United States: adjustable gastric band (AGB), Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion with a duodenal switch (BPD-DS), and vertical sleeve gastrectomy (VSG). Each has its own benefits and risks. To select the option that is best for you, you and your physician will consider that operation’s benefits and risks along with many other factors, including BMI, eating behaviors, obesity-related health conditions, and previous operations.

Adjustable Gastric Band

AGB works primarily by decreasing food intake. Food intake is limited by placing a small bracelet-like band around the top of the stomach to produce a small pouch about the size of a thumb. The outlet size is controlled by a circular balloon inside the band that can be inflated or deflated with saline solution to meet the needs of the patient.

Roux-en-Y Gastric Bypass

RYGB works by restricting food intake and by decreasing the absorption of food. Food intake is limited by a small pouch that is similar in size to the adjustable gastric band. In addition, absorption of food in the digestive tract is reduced by excluding most of the stomach, duodenum, and upper intestine from contact with food by routing food directly from the pouch into the small intestine.

Biliopancreatic Diversion With a Duodenal Switch

BPD-DS, usually referred to as a “duodenal switch,” is a complex bariatric operation that principally includes 1) removing a large portion of the stomach to promote smaller meal sizes, 2) re-routing of food away from much of the small intestine to partially prevent absorption of food, and 3) re-routing of bile and other digestive juices which impair digestion.

In removing a large portion of the stomach, a more tubular “gastric sleeve” (also known as a vertical sleeve gastrectomy, or VSG) is created.

The smaller stomach sleeve remains connected to a very short segment of the duodenum, which is then directly connected to a lower part of the small intestine. This operation leaves a small portion of the duodenum available for food and the absorption of some vitamins and minerals.

However, food that is eaten by the patient bypasses the majority of the duodenum. The distance between the stomach and colon is made much shorter after this operation, thus promoting malabsorption. BPD-DS produces significant weight loss. However, there is greater risk of long-term complications because of decreased absorption of food, vitamins, and minerals.

Vertical Sleeve Gastrectomy

VSG historically had been performed only as the first stage of BPD-DS (see above) in patients who may be at high risk for complications from more extensive types of surgery. These patients’ high risk levels are due to body weight or medical conditions. However, more recent information indicates that some patients who undergo a VSG can actually lose significant weight with VSG alone and avoid a second procedure. It is not yet known how many patients who undergo VSG alone will need a second stage procedure. A VSG operation restricts food intake and does not lead to decreased absorption of food. However, most of the stomach is removed, which may decrease production of a hormone called ghrelin. A decreased amount of ghrelin may reduce hunger more than other purely restrictive operations, such as gastric band.

Complications:

Early complications of these operations can include bleeding, infection, leaks from the site where the intestines are sewn together, and blood clots in the legs that can progress to the lungs and heart.

Examples of complications that may occur later include malnutrition, especially in patients who do not take their prescribed vitamins and minerals. In some cases, if the malnutrition is not addressed promptly, diseases such as pellagra, beri beri, and kwashiorkor may occur along with permanent damage to the nervous system. Other late complications include strictures (narrowing of the sites where the intestine is joined) and hernias.

Two kinds of hernias may occur after a patient has bariatric surgery. An incisional hernia is a weakness that sticks out from the abdominal wall’s fascia (connective tissue) and may cause a blockage in the bowel. An internal hernia occurs when the small bowel is displaced into pockets in the lining of the abdomen. These pockets are created when the intestines are sewn together. Internal hernias are considered more dangerous than incisional ones and need prompt attention to avoid serious complications.

Research indicates that about 10 percent of patients who undergo bariatric surgery may have unsatisfactory weight loss or regain much of the weight that they lost. Some behaviors such as frequent snacking on high-calorie foods or lack of exercise can contribute to inadequate weight loss. Technical problems that may occur with the operation, like a stretched pouch or separated stitches, may also contribute to inadequate weight loss.

Some patients may also require emotional support to help them through the postoperative changes in body image and personal relationships.

Open and Laparoscopic Bariatric Surgery

Bariatric surgery may be performed through “open” approaches, which make abdominal incisions in the traditional manner, or by laparoscopy. With the laparoscopic approach, sophisticated instruments are inserted through 1/2-inch incisions and guided by a small camera that sends images to a television monitor. Most bariatric surgery today is performed laparoscopically because it requires a smaller cut, creates less tissue damage, leads to earlier discharges from the hospital, and has fewer complications, especially postoperative hernias.

However, not all patients are suitable for laparoscopy. Patients who are extremely obese, who have had previous abdominal surgery, or have complicating medical problems may require the open approach.

 Diabetes Overview:

Diabetes is a disease in which the level of glucose (a form of sugar) in the blood is too high. It is a serious disease. If left untreated, it may cause serious complications in eyes, kidneys, nerves, and heart. About 6 percent of Americans have diabetes and two-thirds of people with diabetes die of heart disease.

Causes:

Glucose is a main source of energy for the body. Most of the food we eat is broken down into glucose which then passes into the bloodstream and circulates throughout the body. Glucose can enter some cells directly, such as the cells of the retina, kidney and nervous tissues. However, for most body cells, such as muscle cells (myocytes) and fat cells (adipocytes), insulin is required to move glucose from the bloodstream into the cell.

Insulin is a hormone produced by the pancreas, a large gland behind the stomach. In people with diabetes, either the pancreas does not produce enough insulin or the cells do not use insulin properly, or both. Consequently, glucose builds up in the blood.

There are three main types of diabetes:

Type 1 diabetes

In type 1 diabetes, the immune system attacks the insulin-producing beta cells in the pancreas, which then produces little or no insulin. This type accounts for about 5 to 10 percent of diagnosed diabetes in the United States. It occurs mainly in children and young adults.

Type 2 diabetes

This is the most common form of diabetes. About 90 to 95 percent of people with diabetes have type 2. This form of diabetes is most often associated with older age, obesity, family history of diabetes and physical inactivity. About 80 percent of people with type 2 diabetes are overweight. It usually begins with insulin resistance, a condition in which fat, muscle, and liver cells do not use insulin properly. At first, the pancreas keeps up with the added demand by producing more insulin. In time, however, it loses the ability to secrete enough insulin in response to meals.

Gestational diabetes

Some women develop gestational diabetes late in pregnancy. Although this form of diabetes usually disappears after the birth of the baby, women who have had gestational diabetes have a 40 to 60 percent chance of developing type 2 diabetes within 5 to 10 years. Gestational diabetes is caused by the hormones of pregnancy or a shortage of insulin.

 

Symptoms and Diagnosis

The signs of diabetes are

• increased thirst
• increased urination, especially at night
• increased hunger
• weight loss
• blurred vision
• sores that do not heal

Doctors use the following tests to diagnose diabetes.

• A fasting plasma glucose (FPG) test measures blood glucose in a person who has not eaten anything for at least 8 hours.

• An oral glucose tolerance test (OGTT) measures blood glucose after a person fasts at least 8 hours and 2 hours after the person drinks a glucose-containing beverage.

Test results indicating that a person has diabetes should be confirmed with a second test on a different day.

FPG Test

The FPG test is the preferred test for diagnosing diabetes because of its convenience and low cost. However, it will miss some diabetes or pre-diabetes that can be found with the OGTT. The FPG test is most reliable when done in the morning. Results and their meaning are shown in Table 1. People with a fasting glucose level of 100 to 125 milligrams per deciliter (mg/dL) have a form of pre-diabetes called impaired fasting glucose (IFG). Having IFG means a person has an increased risk of developing type 2 diabetes but does not have it yet. A level of 126 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes.

Table 1. Fasting Plasma Glucose Test

Plasma Glucose Result (mg/dL)	Diagnosis
99 and below	Normal
100 to 125	Pre-diabetes
126 and above	Diabetes

OGTT

Research has shown that the OGTT is more sensitive than the FPG test for diagnosing pre-diabetes, but it is less convenient to administer. The OGTT requires fasting for at least 8 hours before the test. The plasma glucose level is measured immediately before and 2 hours after a person drinks a liquid containing 75 grams of glucose dissolved in water. Results and their meaning are shown in Table 2. If the blood glucose level is between 140 and 199 mg/dL 2 hours after drinking the liquid, the person has a form of pre-diabetes called impaired glucose tolerance (IGT). Having IGT, like having IFG, means a person has an increased risk of developing type 2 diabetes but does not have it yet. A 2-hour glucose level of 200 mg/dL or above, confirmed by repeating the test on another day, means a person has diabetes.

Table 2. Oral Glucose Tolerance Test

2-Hour Plasma Glucose Result (mg/dL)	Diagnosis
139 and below	Normal
140 to 199	Pre-diabetes
200 and above	Diabetes

Treatment

Type 1 Diabetes

Type 2 Diabetes

Gestational Diabetes

 Type 1 Diabetes:

The type 1 diabetes is one of many autoimmune diseases in which the immune system's recognition apparatus breaks down, and the body begins to manufacture T cells and antibodies directed against its own cells and organs. For type 1 diabetes, the misguided T cells attack insulin-producing beta cells in the pancreas, which then produces little or no insulin.

Treatment

Currently, the type 1 diabetes is treated with taking insulin to replace the loss of naturally produced insulin. The insulin treatment must be continued indefinitely to control the level of blood glucose, preventing serious complications. It cannot cure the disease. Researchers are experimenting with pancreatic islet transplantation which, if successful, can cure the type 1 diabetes.

Taking Insulin

Insulin injection is preferred over insulin pill because after insulin pill enters the digestive system, it would be broken down before getting into the blood to lower blood glucose level. Traditionally, patients use a needle and syringe to inject insulin just under the skin. Several other devices for taking insulin are available and new approaches are under development.

Insulin pens

Insulin pens provide a convenient, easy-to-use way of injecting insulin and may be less painful than a standard needle and syringe. An insulin pen looks like a pen with a cartridge. Some of these devices use replaceable cartridges of insulin. Other pens are prefilled with insulin and are totally disposable after the insulin is injected. Insulin pen users screw a short, fine, disposable needle on the tip of the pen before an injection. Then users turn a dial to select the desired dose of insulin, inject the needle, and press a plunger on the end to deliver the insulin just under the skin. Insulin pens are less widely used in the United States than in many other countries.

External insulin pumps

 

External insulin pumps are typically about the size of a deck of cards or cell phone, weigh about 3 ounces, and can be worn on a belt or carried in a pocket. Most pumps use a disposable plastic cartridge as an insulin reservoir. A needle and plunger are temporarily attached to the cartridge to allow the user to fill the cartridge with insulin from a vial. The user then removes the needle and plunger and loads the filled cartridge into the pump.

Disposable infusion sets are used with insulin pumps to deliver insulin to an infusion site on the body, such as the abdomen. Infusion sets include a cannula—a needle or a small, soft tube—that the user inserts into the tissue beneath the skin. Devices are available to help insert the cannula. Narrow, flexible plastic tubing carries insulin from the pump to the infusion site. On the skin’s surface, an adhesive patch or dressing holds the infusion set in place until the user replaces it after a few days.

Users set the pumps to give a steady trickle or “basal” amount of insulin continuously throughout the day. Pumps can also give “bolus” doses—one-time larger doses—of insulin at meals and at times when blood glucose is too high based on the programming set by the user. Frequent blood glucose monitoring is essential to determine insulin dosages and to ensure that insulin is delivered.

Injection ports

Injection ports provide an alternative to daily injections. Injection ports look like infusion sets without the long tubing. Like infusion sets, injection ports have a cannula that is inserted into the tissue beneath the skin. On the skin’s surface, an adhesive patch or dressing holds the port in place. The user injects insulin through the port with a needle and syringe or an insulin pen. The port remains in place for several days and is then replaced. Use of an injection port allows a person to reduce the number of skin punctures to one every few days to apply a new port.

Pancreatic Islet Transplantation

The pancreas, an organ about the size of a hand, is located behind the lower part of the stomach. It makes insulin and enzymes that help the body digest and use food. Spread all over the pancreas are clusters of cells called the islets of Langerhans. Islets are made up of two types of cells: alpha cells, which make glucagon (a hormone that raises the level of glucose in the blood), and beta cells, which make insulin.

In an experimental procedure called islet transplantation, islets are taken from a donor pancreas and transferred into another person. Once implanted, the beta cells in these islets begin to make and release insulin. Researchers hope that islet transplantation will help people with type 1 diabetes live without daily injections of insulin.

 Type 2 Diabetes:

Type 2 diabetes is characterized by insulin resistance. This type accounts for more than 90 percent of diabetes cases. About 80 percent of people with type 2 diabetes are overweight.

Treatment

Type 2 diabetes is presently incurable, but it can be controlled. Strict control of blood glucose is the best defense against the serious complications of diabetes. There are three ways to control blood glucose level: diet, exercise and medications.

Diet

 

The diabetes food pyramid can help you make wise food choices. It divides foods into groups, based on what they contain. Eat more from the groups at the bottom of the pyramid (starches, fruits and vegetables), and less from the groups at the top (fats and sugar).

Exercise

Exercise is especially good for people with diabetes because

• exercise helps keep weight down
• exercise helps insulin work better to lower blood glucose
• exercise is good for heart and lungs.

Medications

Insulin injection and diabetes pills are the two kinds of medicines used to lower blood glucose. There are several different types of diabetes pills, each type helps lower blood glucose in a different way.

• Biguanides block the liver from making sugar.
• Sulfonylureas stimulate pancreas to make more insulin.
• Thiazolidinediones help the body use insulin better.
• Meglitinides stimulate pancreas to make more insulin.
• Alpha-glucosidase inhibitors Slow the digestion of sugar.

Gestational Diabetes

Gestational diabetes is a type of diabetes that is found when a woman is pregnant. During pregnancy, the placenta produces a variety of hormones. Some of them may cause insulin resistance, resulting in diabetes. Out of every 100 pregnant women in the United States, three to eight get gestational diabetes. Although it usually disappears after delivery, the mother is at increased risk of getting type 2 diabetes later in life.

Untreated or uncontrolled gestational diabetes can affect the baby, such as

• being born very large and with extra fat
• low blood glucose right after birth
• breathing problems

Treatment

Treating gestational diabetes means taking steps to keep your blood glucose levels in a target range. That includes

• a meal plan
• physical activity
• insulin (if needed)

Meal Plan

You will talk with a dietitian or a diabetes educator who will design a meal plan to help you choose foods that are healthy for you and your baby. You may be advised to

• limit sweets
• eat three small meals and one to three snacks every day
• be careful about when and how much carbohydrate-rich food you eat
• include fiber in your meals in the form of fruits, vegetables, and whole-grain crackers, cereals, and bread.

Physical Activity

Physical activity, such as walking, swimming and housework, can help you reach your blood glucose targets.

Insulin

Some women with gestational diabetes need insulin, in addition to a meal plan and physical activity, to reach their blood glucose targets.

 Diabetes Complications

Heart Disease and Stroke

If you have diabetes, you are at least twice as likely as someone who does not have diabetes to have heart disease or a stroke. People with diabetes also tend to develop heart disease or have strokes at an earlier age than other people. Two-thirds of people with diabetes die of heart disease.

This is because high blood glucose levels over time can lead to increased deposits of fatty materials on the insides of the blood vessel walls. These deposits may affect blood flow, increasing the chance of clogging and hardening of blood vessels (atherosclerosis).

Diabetic retinopathy

 

This complication occurs in the retina of the eye, resulting from damages to the tiny blood vessels in the retina. The disease develops slowly. First, these tiny blood vessels swell and weaken. Some blood vessels then become clogged and do not let enough blood through. At this stage, you might not have any loss of sight from these changes, but they can be detected by a dilated eye exam.

As the problem gets worse, new blood vessels grow. These new blood vessels are weak. They break easily and leak blood into the vitreous of the eye. The leaking blood keeps light from reaching the retina. You may see floating spots or almost total darkness. Sometimes the blood will clear out by itself. But you might need surgery to remove it.

Over the years, the swollen and weak blood vessels can form scar tissue and pull the retina away from the back of the eye. If the retina becomes detached, you may see floating spots or flashing lights. You may feel as if a curtain has been pulled over part of what you are looking at. A detached retina can cause loss of sight or blindness if you don't take care of it right away.

Chronic Kidney Disease (CKD)

Each year in the United States, more than 100,000 people are diagnosed with kidney failure, a serious condition in which the kidneys fail to rid the body of wastes. Kidney failure is the final stage of chronic kidney disease (CKD).

Diabetes is the most common cause of kidney failure, accounting for nearly 44 percent of new cases. Even when diabetes is controlled, the disease can lead to CKD and kidney failure. Most people with diabetes do not develop CKD that is severe enough to progress to kidney failure. Nearly 24 million people in the United States have diabetes, and nearly 180,000 people are living with kidney failure as a result of diabetes

The function of the kidney is to filter the blood, remove the wastes, and excrete the wastes in the urine. The kidney disease takes many years to develop. In some people, the filtering function of the kidneys is actually higher than normal in the first few years of their diabetes. This process is called hyperfiltration.

Over several years, people who are developing kidney disease will have small amounts of the blood protein albumin begin to leak into their urine. This first stage of CKD is called microalbuminuria. The kidney’s filtration function usually remains normal during this period.

As the disease progresses, more albumin leaks into the urine. This stage may be called macroalbuminuria or proteinuria. As the amount of albumin in the urine increases, the kidneys’ filtering function usually begins to drop. The body retains various wastes as filtration falls. As kidney damage develops, blood pressure often rises as well.

Overall, kidney damage rarely occurs in the first 10 years of diabetes, and usually 15 to 25 years will pass before kidney failure occurs. For people who live with diabetes for more than 25 years without any signs of kidney failure, the risk of ever developing it decreases.

Diabetic neuropathies

Diabetic neuropathies are a family of nerve disorders caused by diabetes. People with diabetes can, over time, develop nerve damage throughout the body. Some people with nerve damage have no symptoms. Others may have symptoms such as pain, tingling, or numbness—loss of feeling—in the hands, arms, feet, and legs. Nerve problems can occur in every organ system, including the digestive tract, heart, and sex organs.

About 60 to 70 percent of people with diabetes have some form of neuropathy. People with diabetes can develop nerve problems at any time, but risk rises with age and longer duration of diabetes. The highest rates of neuropathy are among people who have had diabetes for at least 25 years. Diabetic neuropathies also appear to be more common in people who have problems controlling their blood glucose, also called blood sugar, as well as those with high levels of blood fat and blood pressure and those who are overweight.

Hypoglycemia

Hypoglycemia is a disease in which the blood glucose level drops too low to provide enough energy for the body's activities. Its symptoms include hunger, nervousness and shakiness, sweaty, dizziness, confusion, sleepiness, feeling anxious or weak. For people with diabetes (high blood glucose level), hypoglycemia can be caused by excessive doses of blood-glucose lowering medications (such as insulin), insufficient food, or increased activities.

Erectile Dysfunction (ED)

Erectile dysfunction is the inability to get or keep an erection firm enough for sexual intercourse. ED can be a total inability to achieve an erection, an inconsistent ability to do so, or a tendency to sustain only brief erections.

ED is sometimes called impotence, but that word is being used less often so that it will not be confused with other, nonmedical meanings of the term.

The National Institutes of Health estimates that ED affects as many as 30 million men in the United States. Incidence increases with age: About 4 percent of men in their 50s and nearly 17 percent of men in their 60s experience a total inability to achieve an erection. The incidence jumps to 47 percent for men older than 75. But ED is not an inevitable part of aging. ED is treatable at any age.

ED usually has a physical cause, such as disease, injury, or side effects of drugs. Any disorder that causes injury to the nerves or impairs blood flow in the penis has the potential to cause ED. Diseases—such as diabetes, high blood pressure, nerve disease or nerve damage, multiple sclerosis, atherosclerosis, and heart disease—account for the majority of ED cases.

Insulin, Diabetes and Obesity

Insulin Release and Signaling

Insulin is a peptide consisting of 51 amino acids. It is stored in the secretory granules of beta cells. Glucose may enter beta cells via the glucose transporter (GLUT2) to produce ATP. The beta cell membrane contains ATP-sensitive potassium (K_ATP) channels which are open in the absence of ATP and closed upon ATP binding. The increase in cellular ATP concentration causes more K_ATP channels to close, resulting in membrane depolarization. This in turn opens the voltage-gated Ca²⁺ channels. The influx of Ca²⁺ stimulates the release of insulin from the secretory granules.

The released insulin may circulate through the bloodstream and bind to its receptors on the surface of target cells. The insulin receptor is a receptor tyrosine kinase which, upon activation, phosphorylates the intracellular insulin receptor substrate (IRS). Subsequently, IRS binds various proteins containing the SH2 domain to transmit the signal. The major metabolic actions of insulin is transmitted by PI3K (class IA) via downstream effectors such as PDK1 and Akt.

Insulin Resistance

The type 2 diabetes begins with insulin resistance - a condition in which normal insulin signaling pathways are impaired. About 80 percent of people with type 2 diabetes are associated with obesity. While the detailed mechanism of insulin resistance is not fully understood. It has been well established that adipokines (such as leptin and adiponectin) play an important role. As mentioned in the chapter, Leptin and Obesity, both leptin and adiponectin can activate AMPK to reduce fats. The AMPK activation also has an insulin-sensitizing effect. Therefore, insulin resistance could result from insufficient AMPK activation by leptin and adiponectin in obese people due to leptin resistance and downregulation of adiponectin. This explains why diabetes is often associated with obesity.