DIABETES

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IntroductionDiabetes mellitus is not a single disease entity but

rather a group of metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia in diabetes results from defects in insulin secretion, insulin action, or, most commonly, both. The chronic hyperglycemia and attendant metabolic dysregulation may be associated with secondary damage in multiple organ systems, especially the kidneys, eyes, nerves, and blood vessels.

The total number of people with diabetes worldwide was estimated to be between 151 million and 171 million at the turn of the century, and is expected to rise to 366 million by 2030. The prevalence of diabetes is increasingly sharply in the developing world as people adopt more sedentary life styles, with India and China being the largest contributors to the world's diabetic load.

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National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United States by age (≥20 years of age) 1988-1994 and 1999-2002 4

5National Health and Nutrition Evaluation Survey (NHANES) prevalence of diabetes mellitus in United States by age (≥20 years of age) 1988-1994 and 1999-2002

ClassificationAlthough all forms of diabetes mellitus share

hyperglycemia as a common feature, the underlying abnormalities involved in the development of hyperglycemia vary widely. The previous classification schemes of diabetes mellitus were based on the age at onset of the disease or on the mode of therapy; in contrast, the etiologic classification reflects our greater understanding of the pathogenesis of each variant. The vast majority of cases of diabetes fall into the following classes:

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Diabetes Classification Majority of diabetics classified in 2

categories:type 1: absolute deficiency of insulintype 2: presence of insulin resistance with

reduced insulin secretionGestational diabetes

triggered by stress of pregnancyOther specific types:

infections, drugs, endocrinopathies, pancreatic destruction, genetic defects

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 Classification of Diabetes Mellitus - summary    1.    Type 1 diabetes (β-cell destruction, usually leading to absolute insulin deficiency)

   Immune-mediated   Idiopathic   2.    Type 2 diabetes (combination of insulin resistance and β-cell dysfunction)   3.    Genetic defects of β-cell function    Maturity-onset diabetes of the young (MODY), caused by mutations in:    Hepatocyte nuclear factor 4α (HNF4A), MODY1   Glucokinase (GCK), MODY2   Hepatocyte nuclear factor 1α (HNF1A), MODY3   Pancreatic and duodenal homeobox 1 (PDX1), MODY4   Hepatocyte nuclear factor 1β (HNF1B), MODY5   Neurogenic differentiation factor 1 (NEUROD1), MODY6

   Neonatal diabetes (activating mutations in KCNJ11 and ABCC8, encoding Kir6.2 and SUR1, respectively)   Maternally inherited diabetes and deafness (MIDD) due to mitochondrial DNA mutations (m.3243A→G)   Defects in proinsulin conversion   Insulin gene mutations   4.    Genetic defects in insulin action    Type A insulin resistance   Lipoatrophic diabetes, including mutations in PPARG    5.    Exocrine pancreatic defects    Chronic pancreatitis   Pancreatectomy/trauma   Neoplasia   Cystic fibrosis   Hemachromatosis   Fibrocalculous pancreatopathy 88

   6.    Endocrinopathies    Acromegaly   Cushing syndrome   Hyperthyroidism   Pheochromocytoma   Glucagonoma   7.    Infections    Cytomegalovirus   Coxsackie B virus   Congenital rubella   8.    Drugs    Glucocorticoids   Thyroid hormone   Interferon-α   Protease inhibitors   β-adrenergic agonists   Thiazides   Nicotinic acid   Phenytoin (Dilantin)   Vacor   9.    Genetic syndromes associated with diabetes    Down syndrome   Kleinfelter syndrome   Turner syndrome   Prader-Willi syndrome   10.  Gestational diabetes mellitus

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Type 1 diabetes is an autoimmune disease characterized by pancreatic β-cell destruction and an absolute deficiency of insulin. It accounts for approximately 5% to 10% of all cases, and is the most common subtype diagnosed in patients younger than 20 years of age.

Type 2 diabetes is caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells (“relative insulin deficiency”). Approximately 90% to 95% of diabetic patients have type 2 diabetes, and the vast majority of such individuals are overweight. Although classically considered “adult-onset,” the prevalence of type 2 diabetes in children and adolescents is increasing at an alarming pace

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Pathogenesis of Type I DiabetesType 1 diabetes is an autoimmune disease in which islet

destruction is caused primarily by immune effector cells reacting against endogenous β-cell antigens. Type 1 diabetes most commonly develops in childhood, becomes manifest at puberty, and progresses with age.

Since the disease can develop at any age, including late adulthood, the appellation “juvenile diabetes” is now considered obsolete. Similarly, the older moniker “insulin-dependent diabetes mellitus” has been excluded from the recent classification of diabetes because insulin dependence is not a consistent distinguishing feature. Nevertheless, most patients with type 1 diabetes depend on insulin for survival;

without insulin they develop serious metabolic complications such as ketoacidosis and coma. A rare form of “idiopathic” type 1 diabetes has been described in which the evidence for autoimmunity is not definitive. Here we will focus on the typical immune-mediated type 1 diabetes.

As with most autoimmune diseases, the pathogenesis of type 1 diabetes represents interplay of genetic susceptibility and environmental factors.

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Type 1-continueEpidemiologic studies, such as those

demonstrating higher concordance rates for disease in monozygotic vs dizygotic twins, have convincingly established a genetic basis for type 1 diabetes. More recently, genome-wide association studies have identified multiple genetic susceptibility loci for type 1 diabetes, as well as for type 2 diabetes. Over a dozen susceptibility loci for type 1 diabetes are now known. Of these, by far the most important is the HLA locus on chromosome 6p21; according to some estimates, the HLA locus contributes as much as 50% of the genetic susceptibility to type 1 diabetes.

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Type 1 DM Pathogenesis 1. Preclinical period

immune markers present β-cell destruction

2. Hyperglycemia 80 to 90% of β-cells destroyed

3. Transient remission honeymoon phase

4. Established disease

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Type 1 DM Pathogenesis

Type 1 DMAutoimmune destruction of pancreatic β-cells

~90% of patients have markers of immune β-cell destruction at diagnosis

children & adolescents often have rapid β-cell destruction & present with ketoacidosis

may occur at any ageA subgroup of Type I diabetes is known as

latent autoimmune diabetes in adults (LADA)slowly progressive sufficient insulin secretion to prevent

ketoacidosis for many years

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There is evidence that environmental factors, especially viral infections, may be involved in triggering islet cell destruction in type 1 diabetes. Epidemiologic associations have been reported between type 1 diabetes and infection with mumps, rubella, coxsackie B, or cytomegalovirus, among others. At least three different mechanisms have been proposed to explain the role of viruses in the induction of autoimmunity. The first is “bystander” damage, wherein viral infections induce islet injury and inflammation, leading to the release of sequestered β-cell antigens and the activation of autoreactive cells. The second possibility is that the viruses produce proteins that mimic β-cell antigens, and the immune response to the viral protein cross-reacts with the self-tissue (“molecular mimicry”).

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The third hypothesis suggests that viral infections incurred early in life (“predisposing virus”) might persist in the tissue of interest, and subsequent re-infection with a related virus (“precipitating virus”) that shares antigenic epitopes leads to an immune response against the infected islet cells. This last mechanism, also known as “viral déj vu,” might explain the latency between infections and the onset of diabetes. It is unclear whether any of these mechanisms contribute to β-cell damage, and no causative viral infection is established. In fact, some epidemiologic data and studies of experimental models suggest that infections may be protective; the underlying mechanisms of such a protective effect are unknown. An epidemiologic study has also established no causal association between childhood vaccinations and the risk of developing type 1 diabetes.

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Type 2 DMInsulin resistance, relative lack of insulin

secretionUsually presents with cluster of

abnormalities known as metabolic syndrome:abdominal obesityhypertensiondyslipidemiaelevated PAI-1 levels

Increased macrovascular complication risk

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Pathogenesis of Type II DiabetesType 2 diabetes is a prototypic multifactorial complex

disease. Environmental factors, such as a sedentary life style and dietary habits, unequivocally play a role, as will become evident when the association with obesity is considered. Genetic factors are also involved in the pathogenesis, as evidenced by the disease concordance rate of 35% to 60% in monozygotic twins compared with nearly half that in dizygotic twins. Such concordance is even greater than in type 1 diabetes, suggesting perhaps an even larger genetic component in type 2 diabetes.

The two metabolic defects that characterize type 2 diabetes are (1) a decreased response of peripheral tissues to insulin (insulin resistance) and (2) β-cell dysfunction that is manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemia. Insulin resistance predates the development of hyperglycemia and is usually accompanied by compensatory β-cell hyperfunction and hyperinsulinemia in the early stages of the evolution of diabetes

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Insulin resistance Nonesterified fatty acids (NEFAs): Cross-sectional studies have

demonstrated an inverse correlation between fasting plasma NEFAs and insulin sensitivity. The level of intracellular triglycerides is often markedly increased in muscle and liver tissues of obese individuals, presumably because excess circulating NEFAs are deposited in these organs. Central adipose tissue is more “lipolytic” than peripheral sites, which might explain the particularly deleterious consequences of this pattern of fat distribution. Excess intracellular NEFAs overwhelm the fatty acid oxidation pathways, leading to accumulation of cytoplasmic intermediates like diacylglycerol (DAG) and ceramide. These “toxic” intermediates can activate serine/threonine kinases, which cause aberrant serine phosphorylation of the insulin receptor and IRS proteins.

Unlike tyrosine modification, phosphorylation at serine residues attenuates insulin signaling. Insulin normally inhibits hepatic gluconeogenesis by blocking the activity of phosphoenolpyruvate carboxykinase, the first enzymatic step in this process. Attenuated insulin signaling allows phosphoenolpyruvate carboxykinase to “ramp up” gluconeogenesis. Excess NEFAs also compete with glucose for substrate oxidation, leading to feedback inhibition of glycolytic enzymes, and thereby further exacerbating the existing glucose imbalance. 

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      Adipokines: It is recognized that adipose tissue is not merely a passive storage depot for fat but is a functional endocrine organ that releases hormones in response to changes in the metabolic status. A variety of proteins secreted into the systemic circulation by adipose tissue have been identified, and these are collectively termed adipokines (or adipose cytokines). Both pro-hyperglycemic adipokines (e.g., resistin, retinol binding protein 4 [RBP4]) and anti-hyperglycemic adipokines (leptin, adiponectin) have been identified. Leptin and adiponectin improve insulin sensitivity by directly enhancing the activity of the AMP-activated protein kinase (AMPK), an enzyme that promotes fatty acid oxidation, in liver and skeletal muscle. Adiponectin levels are reduced in obesity, thus contributing to insulin resistance. Notably, AMPK is also the target for metformin, a commonly used oral antidiabetic medication.

    Inflammation: Adipose tissue also secretes a variety of pro-inflammatory cytokines like tumor necrosis factor, interleukin-6, and macrophage chemoattractant protein-1, the last attracting macrophages to fat deposits. Studies in experimental models have demonstrated that reducing the levels of pro-inflammatory cytokines enhances insulin sensitivity. These cytokines induce insulin resistance by increasing cellular “stress,” which in turn, activates multiple signaling cascades that antagonize insulin action on peripheral tissues.

    Peroxisome proliferator-activated receptor γ (PPAR γ): PPARγ is a nuclear receptor and transcription factor expressed in adipose tissue, and plays a seminal role in adipocyte differentiation. A class of antidiabetic medications known as thiazolidinediones acts as agonist ligands for PPARγ and improves insulin sensitivity. Activation of PPARγ promotes secretion of anti-hyperglycemic adipokines like adiponectin, and shifts the deposition of NEFAs toward adipose tissue and away from liver and skeletal muscle. As discussed below, rare mutations of PPARG that cause profound loss of protein function can result in monogenic 2222

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Type 2 DM Risk FactorsBMI ≥ 25Physical inactivity1st degree relative with

DMHigh risk ethnic group

(Latino, African American, Native American, Asian American, Pacific Islander)

IFG, IGTHTN: ≥ 140/90 mmHg

or on therapy for HTN

CV disease HDL < 35 mg/dL Triglycerides > 250

mg/dLDelivery of > 9 lb baby History of GDMInsulin resistance

acanthosis nigricans, severe obesity

Polycystic ovary syndrome

24American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.

Clinical Presentation of Diabetesa

Characteristic  Type 1 DM  Type 2 DM 

Age < 30 yearsb > 30 yearsb

Onset Abrupt Gradual

Body habitus Lean Obese or history of obesity

Insulin resistance Absent Present

Autoantibodies Often present Rarely present

Symptoms Symptomaticc Often asymptomatic

Ketones at diagnosis Present Absentd

Need for insulin therapy Immediate Years after diagnosis

Acute complications Diabetic ketoacidosis

Hyperosmolar hyperglycemic state

Microvascular complications at diagnosis

No Common

Macrovascular complications at or before diagnosis

Rare Common

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aClinical presentation can vary widely. bAge of onset for type 1 DM is generally < 20 years of age but can present at any age. The prevalence of type 2 DM in children, adolescents, and young adults is increasing. This is especially true in ethnic and minority children. cType 1 can present acutely with symptoms of polyuria, nocturia, polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more likely to present with ketones but after the acute phase can treated with oral agents. Prolonged fasting can also produce ketones in individuals.

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition: http://www.accesspharmacy.com/

Diagnosis Blood glucose values are normally maintained in a very

narrow range, usually 70 to 120 mg/dL. The diagnosis of diabetes is established by noting elevation of blood glucose by any one of 4 criteria:   

1.    A random glucose concentration greater than 200 mg/dL, with classical signs and symptoms

2.    A fasting glucose concentration greater than 126

mg/dL on more than one occasion

3.    An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is greater than 200 mg/dL 2 hours after a standard carbohydrate load

4. An Hb A1c level of more than 6.5 %.

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HbA1c (Hemoglobin A1c): gold standard for monitoring glycemic controlHbA1c reflects glucose levels for the previous 2 to 3 months

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Levels of blood glucose proceed along a continuum. Individuals with fasting glucose concentrations less than 100 mg/dL, or less than 140 mg/dL following an OGTT, are considered to be euglycemic. However, those with fasting glucose concentrations greater than 100 mg/dL but less than 126 mg/dL, or OGTT values greater than 140 mg/dL but less than 200 mg/dL, are considered to have impaired glucose tolerance, also known as “pre-diabetes.”

Pre-diabetic individuals have a significant risk of progressing to overt diabetes over time, with as many as 5% to 10% advancing to diabetes mellitus per year. In addition, pre-diabetics are at risk for cardiovascular disease, as a result of the abnormal carbohydrate metabolism as well as the coexistence of other risk factors such as low levels of high-density lipoprotein, hypertriglyceridemia, and increased plasminogen activator inhibitor-1 (PAI-1) 2828

Glucose HomeostasisNormal glucose homeostasis is tightly regulated by three

interrelated processes: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly

skeletal muscle; and actions of insulin and counter-regulatory hormones,

including glucagon, on glucose uptake and metabolism.

Insulin and glucagon have opposing regulatory effects on glucose homeostasis. During fasting states, low insulin and high glucagon levels facilitate hepatic gluconeogenesis and glycogenolysis (glycogen breakdown) while decreasing glycogen synthesis, thereby preventing hypoglycemia. Thus, fasting plasma glucose levels are determined primarily by hepatic glucose output. Following a meal, insulin levels rise and glucagon levels fall in response to the large glucose load. Insulin promotes glucose uptake and utilization in tissues. The skeletal muscle is the major insulin-responsive site for postprandial glucose utilization, and is critical for preventing hyperglycemia and maintaining glucose homeostasis. 2929

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Insulin secretion The insulin gene is expressed in the β cells of the pancreatic islets.

Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps generate mature insulin and a cleavage peptide, C-peptide. Both insulin and C-peptide are then stored in secretory granules and secreted in equimolar quantities after physiologic stimulation; thus, C-peptide levels serve as a surrogate for β-cell function, decreasing with loss of β-cell mass in type 1 diabetes, or increasing with insulin resistance–associated hyperinsulinemia.

The most important stimulus for insulin synthesis and release is glucose itself. A rise in blood glucose levels results in glucose uptake into pancreatic β cells, facilitated by an insulinin-dependent glucose-transporter, GLUT-2. β cells express an ATP-sensitive K+ channel on the membrane, which comprises two subunits: an inward rectifying K+ channel (Kir6.2) and the sulfonylurea receptor (SUR1), the latter being the binding site for oral hypoglycemic agents (sulfonylureas) used in the treatment of diabetes (see next slide). Metabolism of glucose by glycolysis generates ATP, resulting in an increase in β-cell cytoplasmic ATP/ADP ratios. This inhibits the activity of the ATP-sensitive K+ channel, leading to membrane depolarization and the influx of extracellular Ca through voltage-dependent Ca channels. The resultant increase in intracellular Ca stimulates secretion of insulin, presumably from stored hormone within the β-cell granules. This is the phase of immediate release of insulin.

If the secretory stimulus persists, a delayed and protracted response follows that involves active synthesis of insulin. Other factors, including intestinal hormones and certain amino acids (leucine and arginine), also stimulate insulin release, but not its synthesis.

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Structure of human proinsulin and some commercially available insulin analogs. Insulin is shown as the shaded (darker color) peptide chains, A and B. Differences in the A and B chains and amino acid modifications for insulin aspart, lispro, and glulisine are noted

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The relationship between fasting plasma insulin and fasting plasma glucose in 177 normal weight individuals. Plasma insulin and glucose increase together up to a fasting glucose of 140 mg/dL. When the fasting glucose exceeds 140 mg/dL, the β cell makes progressively less insulin, which leads to an overproduction of glucose by the liver and results in a progressive increase in fasting glucose.

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The loss of the incretin effect in type 2 diabetes mellitus. The plasma insulin responses to oral and intravenous glucose in nondiabetic subjects (left figure), compared to patients with diabetes (right figure).

Glucose Tolerance Test

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Blood glucose curves of a normal and a diabetic person after oral administration of 1 g of glucose/kg body weight.

Note the initial raised concentration in the fasting diabetic.

A criterion of normality is the return of the curve to the initial value within 2 hours.

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Relationship between insulin & glucose over course of a day

Insulin actionsInsulin is the most potent anabolic hormone known, with

multiple synthetic and growth-promoting effects. Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body, thus providing an increased source of energy.

These cells are the striated muscle cells (including myocardial cells) and to a lesser extent, adipocytes, which together represent about two thirds of the entire body weight.

Glucose uptake in other peripheral tissues, most notably the brain, is insulin independent.

In muscle cells, glucose is then either stored as glycogen or oxidized to generate ATP. In adipose tissue, glucose is primarily stored as lipid. Besides promoting lipid synthesis, insulin also inhibits lipid degradation in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis, while inhibiting protein degradation. Thus, the anabolic effects of insulin are attributable to increased synthesis and reduced degradation of glycogen, lipids, and proteins. In addition, insulin has several mitogenic functions, including initiation of DNA synthesis in certain cells and stimulation of their growth and differentiation.

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Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage in muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides, glycogen, & protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white arrows. These pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose & glucose to fatty acids occurs primarily in the liver.

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Adipose TissueIncreased glucose entry

Increased fatty acid synthesis

Increased glycerol phosphate synthesis

Activation of lipoprotein lipase

Inhibition of hormone-sensitive lipase

Increased K+ uptake

MuscleIncreased glucose entry

Increased glycogen synthesis

Increased amino acid uptake

Increased protein synthesis in ribosomes

Decreased release of gluconeogenic amino acids

Increased ketone uptake

Increased K+ uptake

LiverDecreased ketogenesis

Increased protein synthesis

Increased lipid synthesis

Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysisGeneralIncreased cell growth

Insulin signaling pathways Elucidation of the insulin signaling pathway has been central to

our understanding of the pathogenesis of diabetes. The insulin receptor is a tetrameric protein composed of two α- and two βsubunits. The β-subunit cytosolic domain possesses tyrosine kinase activity. Insulin binding to the α-subunit extracellular domain activates the β-subunit tyrosine kinase, resulting in autophosphorylation of the receptor and the phosphorylation (activation) of several intracellular substrate proteins, such as the family of insulin receptor substrate (IRS) proteins, which includes IRS1–IRS4 and GAB1.

The substrate proteins, in turn, activate multiple downstream signaling cascades, including the PI-3K and the MAP kinase pathways, which mediate the metabolic and mitogenic activities of insulin on the cell.

Insulin signaling facilitates the trafficking and docking of vesicles containing the glucose transporter protein GLUT-4 to the plasma membrane, which promotes glucose uptake. This process is mediated by AKT, the principal effector of the PI-3K pathway, but also independently by the cytoplasmic protein CBL, which is a direct phosphorylation target of the insulin receptor.

Insulin signaling is attenuated in vivo by several endogenous inhibitors that act along components of the pathway. For example, protein tyrosine phosphatase 1B (PTPN1B) dephosphorylates the insulin receptor and inhibits insulin signaling. The phosphatase PTEN can attenuate insulin signaling by blocking AKT activation by the PI-3K pathway. 4343

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Whole body glucose disposal, a measure of insulin resistance, is reduced 40% to 50% in obese nondiabetic and lean type 2 diabetic individuals. Obese diabetic individuals are slightly more resistant than lean diabetic patients.

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aOverweight/obesity associated with insulin resistance & metabolic syndrome. The presence of abdominal obesity more highly correlated with metabolic risk factors than elevated body-mass index (BMI). bSome male patients can develop multiple metabolic risk factors when waist circumference is only marginally increased; benefit from life-style changes.

Risk Factor Defining LevelAbdominal obesitya

Men (waist circumference)b

> 102 cm (> 40 in.)

Women > 88 cm (> 35 in.)Triglycerides > 1.7 mmol/L (> 150

mg/dL)HDL cholesterol Men < 1.0 mmol/L (< 40

mg/dL) Women < 1.3 mmol/L (< 50

mg/dL)Blood Pressure ≥ 130/≥ 85 mmHgFasting glucose > 6.1 mmol/L ( > 110

mg/dL)

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Clinical features Type 1 diabetes was formerly thought to occur

primarily in those under age 18 but is now known to occur at any age. In the initial 1 or 2 years following the onset of overt type 1 diabetes, the exogenous insulin requirements may be minimal because of ongoing endogenous insulin secretion (referred to as the honeymoon period). Thereafter, any residual β-cell reserve is exhausted and insulin requirements increase dramatically. Although β-cell destruction is a prolonged process, the transition from impaired glucose tolerance to overt diabetes may be abrupt, and is often brought on by an event, such as infection, that is also associated with increased insulin requirements.

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The onset is marked by polyuria, polydipsia, polyphagia, and, when severe, ketoacidosis, all resulting from metabolic derangements. Since insulin is a major anabolic hormone in the body, deficiency of insulin results in a catabolic state that affects not only glucose metabolism but also fat and protein metabolism. Unopposed secretion of counter-regulatory hormones (glucagon, growth hormone, epinephrine) also plays a role in these metabolic derangements. The assimilation of glucose into muscle and adipose tissue is sharply diminished or abolished. Not only does storage of glycogen in liver and muscle cease, but also reserves are depleted by glycogenolysis. The resultant hyperglycemia exceeds the renal threshold for reabsorption, and glycosuria ensues. The glycosuria induces an osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes. The obligatory renal water loss combined with the hyperosmolarity resulting from the increased levels of glucose in the blood tends to deplete intracellular water, triggering the osmoreceptors of the thirst centers of the brain. In this manner, intense thirst (polydipsia) appears. With a deficiency of insulin the scales swing from insulin-promoted anabolism to catabolism of proteins and fats. Proteolysis follows, and the gluconeogenic amino acids are removed by the liver and used as building blocks for glucose. The catabolism of proteins and fats tends to induce a negative energy balance, which in turn leads to increasing appetite (polyphagia), thus completing the classic triad of diabetes: polyuria, polydipsia, and polyphagia. Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always raise the suspicion of diabetes. 4848

Diabetic ketoacidosis Diabetic ketoacidosis is a serious complication of type 1 diabetes

but may also occur in type 2 diabetes, though not as commonly and not to as marked an extent. These patients have marked insulin deficiency, and the release of the catecholamine hormone epinephrine blocks any residual insulin action and stimulates the secretion of glucagon. The insulin deficiency coupled with glucagon excess decreases peripheral utilization of glucose while increasing gluconeogenesis, severely exacerbating hyperglycemia (the plasma glucose levels are usually in the range of 500 to 700 mg/dL). The hyperglycemia causes an osmotic diuresis and dehydration characteristic of the ketoacidotic state. The second major effect of an alteration in the insulin-to-glucagon ratio is activation of the ketogenic machinery. Insulin deficiency stimulates lipoprotein lipase, with resultant breakdown of adipose stores, and an increase in levels of free fatty acids. When these free fatty acids reach the liver, they are esterified to fatty acyl coenzyme A. Oxidation of fatty acyl coenzyme A molecules within the hepatic mitochondria produces ketone bodies (acetoacetic acid and β-hydroxybutyric acid). The rate at which ketone bodies are formed may exceed the rate at which acetoacetic acid and β-hydroxybutyric acid can be utilized by peripheral tissues, leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, systemic metabolic ketoacidosis results. Release of ketogenic amino acids by protein catabolism aggravates the ketotic state. 4949

Diabetic KetoacidosisDiabetic emergencyPrecipitating Factors

insulin omissionillness, infectioninitial DM presentation

Diagnostic laboratory valueshyperglycemiaanion gap acidosisketonemia, ketonuriafluid deficitsNa+, K+ deficits

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Ketogenesis due to insulin deficiency leads to increased serum levels of ketones, ketonuria

Acetoacetate, β-hydroxybutyrate: ketone bodies produced by the liver; organic acids that cause metabolic acidosis

Respiration partially compensates; reduces PCO2: when pH < 7.20, deep, rapid respirations (Kussmaul breathing)

Acetone: minor product of ketogenesis; can smell fruity odor on breath of diabetic ketoacidosis patients

Diabetic KetoacidosisTreatment: restore intravascular volume 1st

normal saline given acutely switch fluids to D5W or D5W1/2NS when glucose

~250 mg/dL hypotonic fluids to replace free H2O

K+ supplementation potassium phosphate often used; no evidence of

benefitsconstant insulin infusion

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Diabetic KetoacidosisFrequent glucose & K+ monitoring essential

K+ must be WNL before insulin is administeredMetabolic improvement: increased serum

bicarbonate & pHGlucose will fall before the anion gap closes

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Hyperosmaolar hyperglycemic crisis Type 2 diabetes mellitus may also present with polyuria and

polydipsia, but unlike in type 1 diabetes, patients are often older (over 40 years) and frequently obese. However, with the increase in obesity and sedentary life style in our society, type 2 diabetes is now seen in children and adolescents with increasing frequency. In some cases medical attention is sought because of unexplained weakness or weight loss. Most frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic persons. The infrequency of ketoacidosis and milder presentation in type 2 diabetes is presumably because of higher portal vein insulin levels in these patients than in type 1 diabetics, which prevents unrestricted hepatic fatty acid oxidation and keeps the formation of ketone bodies in check. In the decompensated state, these patients may develop hyperosmolar nonketotic coma due to severe dehydration resulting from sustained osmotic diuresis (particularly in patients who do not drink enough water to compensate for urinary losses from chronic hyperglycemia). Typically, the patient is an elderly diabetic who is disabled by a stroke or an infection and is unable to maintain adequate water intake. Furthermore, the absence of ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) delays the seeking of medical attention until severe dehydration and coma occur.

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Hyperosmolar Hyperglycemia Diabetic emergencyTypically older type 2 DM patients Fluid deficits & blood glucose concentrations

generally greater than DKAPrecipitating Factors

infection/illnessprolonged hyperglycemiadehydrationrenal insufficiency

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Hyperosmolar Hyperglycemia Lower blood glucose levels graduallyTreatment

Fluid replacement hypotonic fluids (0.45% saline) should be used if

serum sodium > 150 meq/Llow-dose insulin infusions (1 to 2 units/hour)

Avoid rapid correction of glucose levels no greater than 75 to 100 mg/dLmay result in cerebral edema

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