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.