Ch 22 part 2

Chronic Complications of Diabetes Mellitus Irreversibility of glucose binding to proteins

AGE/RAGE

Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNKS)

AKA hyperglycemic hyperosmolar state Life-threatening emergency Usually associated with type 2 diabetes Similar increase in counter-regulatory hormones in HHNKS and DKA Insulin deficiency: less profound in HHNKS than DKA Fluid deficiency: more marked in HHNKS than DKA Elevated glucose levels: more marked in HHNKS than DKA

Hyperaldosteronism Primary (Conn syndrome, primary hyperaldosteronism)

Abnormality of the adrenal cortex, including adenoma, nodular hyperplasia, and carcinoma

Diabetic Ketoacidosis Insulin deficiency results in reduced glucose uptake, increased fat mobilization with the release of fatty acids, and accelerated ketogenesis leading to DKA

Accumulation of ketone bodies causes a drop in pH and triggers the buffering system associated with metabolic acidosis

Diabetic Ketoacidosis Tx

Administration of insulin to decrease glucose levels immediately and to reduce ketone levels more gradually Fluids Replacement of electrolytes

Disorders of the adrenal cortex Hypofunction of the adrenal cortex

Adrenal insufficiency

Stroke tx

Aggressive management of blood pressure, hyperglycemia, and dyslipidemia

Diabetic Ketoacidosis

An absolute or relative deficiency of insulin and an increase in insulin counter-regulatory hormones Most common in type 1 diabetes mellitus because insulin is more deficient Precipitating factors involve intercurrent illness such as infection, trauma, surgery, or myocardial infarction Insulin deficiency results in reduced glucose uptake, increased fat mobilization with the release of fatty acids, and accelerated ketogenesis leading to DKA

Type 2 Diabetes Mellitus Amylin

Another beta cell hormone that is reduced in types 1 and 2 diabetes Increases satiety and suppresses glucagon release from the alpha cells Contributes to islet cell destruction through the deposition of misfolded amyloid polypeptide in the pancreas

Congenital Adrenal Hyperplasia

Autosomal recessive disorder: 21 hydroxylase enzyme for cortisol biosynthesis is deficient in 90% of cases Cortisol and aldosterone production is low. ACTH is increased.

Diabetic Neuropathies Peripheral neuropathy: distal portions of the neurons are initially and eventually more severely affected

Axonal and Schwann cell degeneration

Type 2 Diabetes Mellitus (Cont.) Beta cell dysfunction

Beta cell mass is decreased. Remaining beta cells become exhausted from long-term demand for elevated insulin biosynthesis.

A person has Cushing syndrome. Which pathophysiologic effect is occurring?

Chronic exposure to excess cortisol

Cushing Disease and Cushing Syndrome Cushing syndrome

Chronic exposure to excessive endogenous cortisol level and is more common in women Lose diurnal and circadian patterns of ACTH and cortisol secretion Lack of ability to increase ACTH and cortisol in response to stressors

Mechanisms Type 2 Diabetes Mellitus (Cont.) Obesity-associated hyperinsulinemia and impaired insulin receptor signaling.

Compensatory hyperinsulinemia prevents the clinical appearance of diabetes for many years

Chronic Complications of Diabetes Mellitus Macrovascular disease

Coronary artery disease MI Cerebral vascular disease Peripheral vascular disease

Disorders of the adrenal cortex Hyperfunction that increases cortisol

Cushing disease Cushing syndrome

Chronic Complications of Diabetes Mellitus Microvascular disease

Diabetic retinopathy Diabetic nephropathy Diabetic neuropathies

Somogyi Effectand Dawn Phenomenon Dawn phenomenon

Early morning glucose elevation Related to nocturnal growth hormone elevation Treatment: increase dose of evening insulin

Cushing Disease and Cushing Syndrome Cushing disease

Excess endogenous secretion of ACTH By a pituitary adenoma (most common) By an ectopic secreting tumor, like a small cell lung carcinoma Secretion of both cortisol and adrenal androgens is increased, and corticotropin-releasing hormone (CRH) secretion is inhibited

Chronic Complications of Diabetes Mellitus (Cont.) Mechanisms Hyperglycemia and the polyol pathway

Excessive accumulation of sorbitol (a polyol sugar alcohol), which is osmotically active and causes tissue edema Reduces glutathione, an antioxidant, contributing to oxidative injury

Hyperaldosteronism

Excessive aldosterone secretion by the adrenal cortex Primary (Conn syndrome, primary hyperaldosteronism) Secondary (secondary hyperaldosteronism)

Type 2 Diabetes Mellitus (Cont.) Tx

Exercise diet treatment of obesity oral hypoglycemics, bariatric surgery

Type 2 Diabetes Mellitus (Cont.) Clinical manifestations are often nonspecific

Fatigue, pruritus recurrent infections visual changes symptoms of neuropathy (paresthesia or weakness) (Other clinical manifestations to consider are that the affected individual is often overweight, dyslipidemic, hyperinsulinemic, and hypertensive) (Classic symptoms of polyuria and polydipsia may present, but they develop more quickly in type 1 than in type 2 diabetes.)

Diabetic Retinopathy Macular edema

Fluid accumulation and retinal thickening near the center of the macula that causes blurring of vision

Other Specific Types of Diabetes Mellitus

Genetic diseases Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced beta cell dysfunction Maturity onset diabetes of youth (MODY)

Diabetic Kidney Disease Progressive changes

Glomerular enlargement, glomerular basement membrane thickening, which results in glomerulosclerosis, loss of podocytes, and reduced GFR later in the disease process

Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNKS) Clinical manifestations

Glycosuria, polyuria, dehydration, and neurologic changes such as stupor Laboratory findings Glucose: often more than 600 mg/dL Absent or low urine and serum ketones -----Lack of ketoacidosis

Gestational Diabetes Mellitus

Has been defined as any degree of glucose intolerance with the onset or first recognition occurring during pregnancy ADA Recommendation: high-risk women who are found to have diabetes at their initial prenatal visit receive a diagnosis of overt diabetes With gestational diabetes mellitus, the risk for type 2 diabetes and long-term metabolic and cardiovascular complications later in life increase for both the mother and the baby.

Alterations of Adrenal Function Disorders of the adrenal cortex

Hyperfunction or hypofunction

Alterations of Adrenal Function (Cont.) Disorders of the adrenal cortex

Hyperfunction that increases cortisol Hyperfunction that increases androgens and estrogen Hyperfunction that increases aldosterone Hypofunction of the adrenal cortex

Acute Complications of Diabetes Mellitus

Hypoglycemia Diabetic ketoacidosis (DKA) Hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) Morning hyperglycemia

A patient with diabetes arrives at the emergency department after an abrupt decrease in level of consciousness. The person has tachycardia, diaphoresis, irritability, tremors, and confusion. The clinician suspects the person has

Hypoglycemia produces sympathetic nervous system activation (tachycardia, diaphoresis, tremors) and reduced delivery of glucose to the brain (confusion, reduced level of consciousness).

Somogyi Effectand Dawn Phenomenon Somogyi effect

Hypoglycemia with rebound hyperglycemia Counter-regulatory hormones cause gluconeogenesis Treatment: reduce the dose of evening insulin Becoming less common due to increasing use of long-acting insulin

Infection Risk for infection increases for several reasons

Impaired senses lead to loss of protection with injury Hypoxia: glycosylated hemoglobin impedes the release of oxygen to the tissues Rapid replication of pathogens from increased glucose in body fluids Reduced blood supply decreases WBC delivery Suppressed immune response: chronic hyperglycemia impairs the innate and adaptive immune responses Delayed wound healing: slower collagen synthesis and reduced angiogenesis increase the opportunity for infection

Chronic Complications of Diabetes Mellitus (Cont.) Mechanisms Hyperglycemia and protein kinase C

Inappropriately activated intracellular signaling protein that may contribute to the microvascular complications of diabetes

Peripheral Artery Disease

Incidence increases in those with diabetes (especially type 2), for peripheral arterial disease (PAD) with claudication, ulcers, gangrene, and amputation. Age, duration of diabetes, glycemic control, genetics, smoking, dyslipidemia, and hypertension are risk factors. Occlusions of small arteries/arterioles (especially below the knee) cause gangrenous changes of lower extremities.

Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNKS) Treatment

Insulin infusion combined with fluid repletion Dehydration in HHNKS is far more severe than in DKA Electrolyte replacement Potassium depletion may be severe and require several days of treatment

Gestational Diabetes Mellitus Contributing factors

Insulin resistance and inadequate insulin secretion both before and during pregnancy

Microvascular Disease

Is a disease in the capillaries caused by diabetes that results in blindness, end-stage kidney failure, and various neuropathies Characteristics of diabetic microangiopathy

Type 2 Diabetes Mellitus

Is more common than type 1 diabetes mellitus Risk factors -----Age, obesity, hypertension, physical inactivity, and family history; metabolic syndrome Affects both adults and children Genetic, epigenetic, and environmental interactions: more than 65 genes associated with type 2 diabetes Insulin resistance and decreased insulin secretion by beta cells are major mechanisms

Diabetic Retinopathy

Is the leading cause of blindness worldwide Develops more rapidly in type 2 diabetes due to the likelihood of long-standing hyperglycemia prior to diagnosis Maculopathy Macular edema

Diabetic Neuropathies

Is the most common complication of diabetes Nerves do not require insulin for glucose transport and are especially vulnerable to the pathologic effects of chronic hyperglycemia Sensory deficits generally precede motor involvement Peripheral neuropathy: distal portions of the neurons are initially and eventually more severely affected Distal symmetrical polyneuropathy: includes large and small nerve fibers

Stroke

Is twice as common in those with diabetes(especially, type 2) and more common in diabetic women. Survival rate for people with diabetes after a massive stroke is typically shorter than for a person without diabetes. Hypertension, hyperglycemia, hyperlipidemia, thrombosis, and sleep apnea are risk factors.

Cardiovascular Disease

Is ultimate cause of death in up to 68% of people with diabetes with higher risk for women Increases with the duration but not the severity of diabetes Is a consequence of accelerated atherosclerosis, hypertension, and increased risk for thrombus formation Can result in coronary artery disease (CAD), congestive heart failure, and myocardial infarction Cardiomyopathy and heart failure are also higher in people with diabetes. Guidelines have been developed to reduce the risk and improve the treatment of CVD in people with diabetes.

Diabetic Retinopathy tx

Laser treatment, vitrectomy, intravitreal steroids, antivascular endothelial growth factor, and renin-angiotensin system inhibitors

Peripheral Artery Disease Occlusions of small arteries/arterioles (especially below the knee) cause gangrenous changes of lower extremities.

Lesions begin as ulcers Progress to osteomyelitis or gangrene Amputation

Macrovascular Disease

Lesions develop in large- and medium-sized arteries from hyperglycemia. Increases risk for hypertension, accelerated atherosclerosis, CVD, stroke, and PVD Advanced glycation end products (AGE) attach to their receptor for AGE (RAGE) in the walls of blood vessels.

Hypoglycemia

Lowered plasma glucose level - Newborns: less than 47 mg/dL - Children and adults: less than 70 mg/dL Called insulin shock or insulin reaction in diabetes

Type 2 Diabetes Mellitus Risk factors Age, obesity, hypertension, physical inactivity, and family history; metabolic syndrome

Metabolic syndrome: abdominal obesity, dyslipidemia (high TG and/or low HDL-C), prehypertension, and impaired fasting glucose confer a high risk of developing type 2 diabetes and CVD

Chronic Complications of Diabetes Mellitus

Microvascular disease Macrovascular disease Infection Cancer Others

Infection

Morbidity and mortality from infectious agents increase in those with diabetes. Risk for infection increases for several reasons

Diabetic Kidney Disease

Most common cause of chronic kidney disease and end-stage kidney disease Progressive changes Microalbuminuria is the first manifestation

Alterations of Adrenal Function Disorders of the adrenal medulla

No known hypofunction Hyperfunction: causes clinically defined syndromes (caused by pheochromocytomas or sympathetic paragangliomas that continuously secrete catecholamines.)

Type 2 Diabetes Mellitus (Cont.) Mechanisms

Obesity-related alteration in the production of adipokines by adipose tissue: increased leptin levels and reduced adiponectin levels contribute to reduced insulin synthesis and insulin resistance Obesity-related elevations in serum free fatty acids and intracellular TG and cholesterol deposits yield lipotoxicity Obesity causes release of such inflammatory cytokines as TNF-α and IL-6 from adipose tissue Obesity-related reductions in insulin-stimulated mitochondrial activity, especially in skeletal muscle and liver tissue Obesity-associated hyperinsulinemia and impaired insulin receptor signaling.

Microvascular Disease Characteristics of diabetic microangiopathy

Occlusion of capillaries with thickening of the capillary basement membrane, endothelial cell hyperplasia, thrombosis, and pericyte degeneration Hypoxia and ischemia accompany microvascular disease, especially in the eye, kidney, and nerves Long duration of asymptomatic hyperglycemia generally precedes diagnosis ----Underscores the need to screen for diabetes

Hypoglycemia tx

Oral or IV glucose Glucagon: prescribed for emergency use for high-risk individuals

Chronic Complications of Diabetes Mellitus (Cont.) Mechanisms Oxidative stress

Overproduction of reactive oxygen species (ROS), which damage large and small vessels

Chronic Complications of Diabetes Mellitus (Cont.) Mechanisms

Oxidative stress Hyperglycemia and the polyol pathway Hyperglycemia and protein kinase C Irreversibility of glucose binding to proteins Hyperglycemia and the hexosamine pathway

Type 2 Diabetes Mellitus (Cont.) Glucagon

Pancreatic alpha cells are less responsive to glucose inhibition High glucagon levels increase hepatic glycogenolysis, gluconeogenesis, thereby exacerbating hepatic glucose production and hyperglycemia. High glucagon levels increase hepatic lipolysis, thereby stimulating ketogenesis

Diabetic Ketoacidosis (Cont.) Clinical manifestations

Polyuria dehydration thirst Kussmaul respirations (hyperventilation to compensate for acidosis) acetone breath odor postural dizziness; CNS depression; anorexia, nausea, vomiting, and abdominal pain

Other Specific Types of Diabetes Mellitus Maturity onset diabetes of youth (MODY)

Presents as non-insulin requiring diabetes in lean individuals typically younger than 25 years of age Includes six specific autosomal dominant mutations (MODY1-MODY6) Diagnosis is based on family history of diabetes with an autosomal dominant mode of inheritance, insulin independence, and age at onset younger than 25 years Genetic testing confirms the diagnosis Management is like those techniques used for type 2 diabetes

Disorders of the adrenal cortex Hyperfunction that increases aldosterone

Primary or secondary hyperaldosteronism

Gestational Diabetes Mellitus Has been defined as any degree of glucose intolerance with the onset or first recognition occurring during pregnancy

Problem is that many were undiagnosed diabetics who had progressive disease after diagnosis

Diabetic Retinopathy Maculopathy

Progressive process that accompanies retinal capillary permeability, vessel occlusion, and ischemia

Macrovascular Disease Advanced glycation end products (AGE) attach to their receptor for AGE (RAGE) in the walls of blood vessels.

Promotes oxidative stress (increasing oxidized LDL), inflammation, endothelial and vascular smooth muscle dysfunction, and thrombosis

Type-2 Diabetes Question Obesity is present in 60%-80% of patients with type 2 diabetes and is a major contributor to insulin resistance by many mechanisms including:

Reduced insulin-stimulated mitochondrial activity

Gestational Diabetes Mellitus With gestational diabetes mellitus, the risk for type 2 diabetes and long-term metabolic and cardiovascular complications later in life increase for both the mother and the baby.

Repeat screening and risk factor management are needed for those with normal postpartum oral glucose tolerance

Type 2 Diabetes Mellitus (Cont.) Insulin resistance

Response of insulin-sensitive tissues (especially liver, skeletal muscle, and adipose tissue) to insulin is suboptimal, yielding inadequate inhibition of hepatic glucose output, inadequate inhibition of adipocyte lipolysis, and inadequate stimulation of glucose uptake and storage in skeletal muscle.

Diabetic Ketoacidosis ADA Criteria for Diagnosis

Serum glucose >250 mg/dL; serum bicarbonate <18 mg/dL; serum pH <7.30; presence of an anion gap; presence of serum and urine ketones

Cushing Disease and Cushing Syndrome Cushing-like syndrome

Side effect of long-term pharmacologic administration of glucocorticoids

Diabetic Neuropathies Distal symmetrical polyneuropathy: includes large and small nerve fibers

Small fiber involvement: neuropathic pain, loss of sensation, and high risk for foot ulceration with subsequent gangrene and amputation Large fiber involvement: sensory loss of proprioception, loss of coordination, and risk for falls

Acute Complications of Diabetes Mellitus Morning hyperglycemia

Somogyi effect Dawn phenomenon Poor glycemic control

Hypoglycemia Clinical manifestations

Tachycardia palpitations diaphoresis tremors pallor arousal anxiety

Diabetic Kidney Disease tx

Tight glucose control and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers can reduce proteinuria and slow the progression of nephropathy Aggressive treatment of hypertension can reduce proteinuria

Disorders of the adrenal cortex Hyperfunction that increases androgens and estrogen

Virilization or feminization

Cushing Disease and Cushing Syndrome (Cont.) Clinical manifestations

Weight gain from adipose tissue accumulation in the trunk, facial, and cervical areas -----Is described as "truncal [central] obesity," "moon face," and "buffalo hump" Sodium and water retention, glucose intolerance, and protein wasting Renal stones Purple striae Bronze or brownish hyperpigmentation of the skin

Type 2 Diabetes Mellitus (Cont.) As for treatment, prevention of type 2 diabetes, especially in those with prediabetes hinges on diet and exercise. Obesity treatment and sustained weight loss results in improved insulin sensitivity and glucose tolerance, preserves beta cell function, and has an inhibitory effect on progression to type 2 diabetes. Diet should match

activity levels and include more complex carbohydrates rather than simple sugars, foods low in fats, adequate protein, and fiber. Bariatric surgery may be indicated for individuals with morbid obesity. Exercise reduces postprandial blood glucose levels, lowers insulin requirements, lowers triglyceride levels, and increases HDL levels.

Congenital Adrenal Hyperplasia ACTH is increased. causes

adrenal hyperplasia: glucocorticoid and mineralocorticoid deficiency and adrenal androgen synthesis -------Affected female infants are virilized. -------Infants of both genders exhibit salt wasting due to low aldosterone levels, resulting in excess sodium loss in the urine.

Type 2 Diabetes Mellitus (Cont.) TNF-α and IL-6 induce insulin resistance through a postreceptor mechanism and play

an important role in the genesis of fatty liver, atherosclerosis, and dyslipidemia.

Type 2 Diabetes Question Lipolysis has a ketogenic effect caused by the metabolism of free fatty acids in the liver and is stimulated by glucagon. Amylin is a peptide hormone cosecreted with insulin in response to nutrients stimuli. It regulates

blood glucose by delaying nutrient uptake and suppressing glucagon secretion after meals. Somatostatin is produced in the pancreas and is a hormone essential in carbohydrate, fat, and protein metabolism. It inhibits the secretion of insulin, glucagon, and pancreatic polypeptide. Grehlin levels increase before a meal and stimulate appetite, then fall soon after a meal and promote a feeling of satiety.

The pancreas, adipose tissue, liver, digestive system, kidney, skeletal muscle, and brain all

contribute to chronic hyperglycemia

The kidney contributes to

hyperglycemia by increases in glucose reabsorption

The liver contributes to

hyperglycemia by increases in hepatic gluconeogenesis and hepatic glucose output

The brain contributes to

hyperglycemia by neurotransmitter dysfunction, altered insulin signaling, and altered lipid sensing.

The digestive system contributes to

hyperglycemia by reductions in glucagon-like peptide-1 and ghrelin

Skeletal muscle contributes to

hyperglycemia by reductions in insulin-stimulated glucose uptake and storage

Comparison of Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic Nonketotic Syndrome compares diabetic ketoacidosis (DKA) on the left to hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) on the right. Again, DKA is marked by a more profound insulin insufficiency coupled with an elevation in counter-regulatory or stress hormones, which results in excessive lipolysis, leading to the formation of ketoacids, which precipitates metabolic acidosis and hyperventilation as a compensatory response. DKA also yields

hyperglycemia, polyuria, dehydration, thirst, and polydipsia. The hyperosmolar hyperglycemic nonketotic syndrome (HHNKS) has a more moderate insulin insufficiency coupled with a counter-regulatory or stress hormone response that yields a more profound hyperglycemia, polyuria, dehydration, thirst, and polydipsia in the absence of ketoacidosis.

Adipose tissue contributes to hyperglycemia by reductions

in insulin-stimulated glucose uptake, increases in lipolysis, increases in leptin secretion, reductions in adiponectin secretion, and increases in TNF-alpha and IL-6 secretion.

the pathophysiology of type 2 diabetes where a genetic predisposition for both type 2 diabetes and obesity interacts with such environmental triggers as diet and physical inactivity. We have already discussed how obesity-related changes

in leptin, adiponectin, free fatty acids, TNF-α, and IL-6 contribute to insulin resistance and reductions in beta cell mass and function. The tissue resistance to insulin results in a compensatory hyperinsulinemia that prevents the onset of diabetes until the reduction of beta cell mass and beta cell exhaustion result in the onset of Type 2 diabetes.

Type-2 Diabetes Question Alterations in oxidative phosphorylation in cellular mitochondria have been documented resulting in reduced insulin-stimulated mitochondrial activity and insulin resistance. Obesity causes release of inflammatory cytokines from adipocytes and from activated macrophages. These cytokines induce

insulin resistance. Elevated free fatty acids are found in obese individuals and binds to receptors which modulate several responses. These changes decrease tissue responses to insulin and promote inflammation. Obesity is correlated with hyperinsulinemia and decreased insulin receptor density.

Type 2 Diabetes Mellitus (Cont.) Lipotoxicity interferes with

intracellular insulin signaling, reduces tissue responses to insulin, alters incretin action, promotes inflammation, and causes apoptotic beta-cell death.

Cushing Disease and Cushing Syndrome tx

medication, radiation, surgery

Type 2 Diabetes Mellitus (Cont.) The treatment goal for those with type 2 diabetes is the restoration of near euglycemia and correction of related metabolic disorders. For those who require further intervention, oral hypoglycemics are indicated. Metformin, which

reduces hepatic glucose production and improves insulin sensitivity, is considered the primary pharmacologic choice for type 2 diabetes and a GLP-1 receptor agonist or basal insulin is added if the HbA1C target is not maintained over 3 months. There are standards of care to guide the management of type 2 diabetes.

The pancreas contributes to hyperglycemia by

reductions in beta cell insulin and amylin secretion as well as increased alpha cell secretion of glucagon.

The myriad consequences of chronic hyperglycemia include

retinopathy neuropathy hypertension peripheral vascular disease stroke heart disease steatohepatitis gastroparesis nephropathy glomerulosclerosis chronic kidney disease, mmunosuppression infection cancer.

Chronic intracellular hyperglycemia also causes

shunting of intracellular glucose into the hexosamine pathway and leads to O-linked glycosylation of several proteins with alterations in signal transduction pathways and oxidative stress.

Type 2 Diabetes Question Glucagon excess may be nearly as important as insulin insufficiency of diabetes because glucagon

stimulates lipolysis.

Type 2 Diabetes Mellitus Pathophysiology we have not yet discussed how hormones released from the gastrointestinal tract contribute to type 2 diabetes. Ghrelin is a peptide produced in the stomach and pancreatic islets that regulates food intake, energy balance, and hormonal secretion. Reduced ghrelin levels have been associated with insulin resistance and increased fasting insulin levels. Its use as a potential treatment for type 2 diabetes is under investigation. The incretins are a class of peptides that are released from the GI tract in response to food intake and function to increase the

synthesis and secretion of insulin and beta cell proliferation and regeneration, and protection against beta cell damage. The most studied incretin is glucagon-like peptide-1 (GLP-1), and studies have demonstrated that beta cell responsiveness to GLP-1 is reduced in both prediabetes and type-2 diabetes. Glucagon-like peptide-1 receptor agonists are approved drug treatments for type-2 diabetes and are also known as incretin mimetics. In addition, gastric bypass surgery greatly enhances the release of GLP-1 release, which improves insulin secretion and beta cell sensitivity to oral glucose. The improved release of GLP-1 after gastric bypass is due to the rapid transit of food from the gastric pouch to the distal ileum.

In those whose diabetes has progressed without

treatment, symptoms related to coronary artery, peripheral artery, and cerebrovascular disease may develop.