A. Normal Glucose Control [3]

1. The normal plasma glucose concentration is maintained in a narrow range
   1. Normal daily glucose varies from 3.5-7.0 mmol/L (~60-120mg/dL)
   2. This is despite wide variations in nutritional intake, exercise, many other factors
   3. Glucose is moved into cells through at least 5 glucose transporters
   4. Thus, glucose homeostasis is a highly regulated process
2. During "fasting" (post-absorptive), endogenous glucose production and use are nearly equal
3. Post-Prandial Glucose
   1. Plasma glucose levels rise to a peak 30-60 minutes after eating
   2. Glucose levels return to baseline within 2-3 hours after eating
   3. Humans demonstrate a continuum of "normal" responses to glucose loads
   4. Regulation of glucose depends on insulin levels, receptor functions, glucagon, others
   5. Impaired responses to insulin may lead to several clinical conditions
4. Insulin
   1. Produced by ß-cells in the islets of Langerhans in the pancreas
   2. Mature insulin consists of A and B chains connected by disulfide bond
   3. Insulin secretion is stimulated by high glucose levels
   4. Insulin secretion is inhibited by low glucose levels and by somatostatin
   5. Plasma insulin levels typically follow the same course of glucose
   6. Insulin binds primarily to the insulin receptor (InsR)
5. Glucagon
   1. Produced by alpha-cells in the islets of Langerhans in the pancreas
   2. Increased secretion in hypoglycemic states
   3. Stimulates production and release of glucose from liver
6. Both insulin and glucagon are required to maintain normal glucose homeostasis

B. Insulin Receptor Signalling

1. Insulin Receptor
   1. InsR consists of 4 chains disuflide linked, 2 alpha and 2 beta subunits
   2. The InsR alpha chains are 135K, external and contain Insulin binding domains
   3. The ß-chains are 95K, transmembrane spanning, with ATP binding and kinase domains
   4. The ß-subunit kinase activity autophosphorylates and is specific for tyrosine
   5. Insulin also binds to the insulin-like growth factor (IGF) receptor
2. Insulin Binding to InsR
   1. Leads to InsR phosphorylation of InsR and other proteins
   2. These other proteins are called InsR substrates 1 through 4 (IRS-1 thorugh -4)
   3. IRS proteins interact with IRS docking adapter proteins after phosphorylation
   4. A variety of growth and regulatory proteins interact with Insulin through the IRS
   5. MAP kinase, PI-3 kinase, PK B, and other pathways are activated
3. InsR and Glucose Transport (see below) [5]
   1. Some of the IRS and adapter proteins interact with the glucose transporters
   2. Four glucose transport proteins are currently known
   3. The main mechanism by which insulin increases glucose transport is by recruitment of intracellular glucose transport proteins to the plasma membrane
   4. Recruitment of GLUT4 transporter to plasma membrane is defective in diabetes
4. Monogenic Disorders of Insulin System [6]
   1. Mutations in insulin or InsR are rare in patients with resistance syndromes or diabetes
   2. Homozygous mutations in InsR causes severe insulin resistance, growth retardation
   3. This syndrome is called Leprechaun syndrome
   4. Glucokinase deficiency (heterozygous mutations) leads to greatly reduced insulin secretion, reduced birthweight, and adult insulin resistance
   5. Pancreatic agenesis is due to homozygous mutations in gene for insulin promoter factor 1 resulting in no fetal insulin secretion
5. Premature infants have isolated reduction in insulin sensitivity [7]
6. "Fast Food" consumption increases weight gain and insulin resistance [8]

C. Glucose Transporters [5]

1. Essentially all organs use glucose
   1. Brain uses a great deal of glucose
   2. Kidney as well
2. Key Organs for glucose level regulation (insulin action sites)
   1. Liver
   2. Skeletal muscle
   3. Adipose Tissue
3. Types of Glucose Transporters
   1. Five known facilitated-diffusion glucose transporters, GLUT-1 through 5
   2. Sodium-linked glucose transporter in intestine and kidney
4. GLUT-1
   1. High concentrations in brain, red blood cells and endothelium
   2. Km glucose ~20mM
   3. Constitutive glucose transporter
5. GLUT-2
   1. High concentrations in kidney, small intestine, liver, pancreatic ß-cells
   2. Km glucose ~42mM
   3. Low affinity glucose transporter
   4. Main role appears to be sensing glucose concentrations in islets
6. GLUT-3
   1. High concentrations in neurons and placenta
   2. Km glucose ~10mM
   3. High affinity glucose transporter
7. GLUT-4
   1. High concentrations in skeletal and cardiac muscle cells and adipocytes
   2. Km glucose ~2-10mM
   3. Insulin responsive glucose transporter
   4. Translocates from intracellular vesicles to plasma membrane on insulin signalling
   5. Muscle is the principle site for insulin stimulated glucose transport
8. GLUT-5
   1. High concentrations in small intestine, sperm, kidney, brain, adipocytes, myocytes
   2. This is a fructose transporter
   3. Very low affinity for glucose

D. Metabolic Syndrome and Other Hyperglycemic Conditions

1. Insulin Resistance Syndromes (IRS) [3]
   1. IRS also called cardiovascular dysmetabolic syndromes or Metabolic Syndrome
   2. Previously called "Syndrome X"
   3. Includes any or all of the following:
   4. Insulin resistance (required)
   5. Hyperinsulinemia
   6. Diabetes mellitus Type 2 (DM2)
   7. Obesity
   8. Hypertension (HTN)
   9. Hypertriglyceridemia
   10. Dyslipidemias: small dense LDL (low density lipoprotein), low HDL (high density lipoprotein)
   11. Hypercoagulability: associated with impaired fibrinolysis
   12. All of these contribute to endothelial dysfunction and atherosclerosis
   13. Elevated HbA1c levels associated with increased CV events with or without DM [9,10]
   14. Elevated levels of oxidized LDL associated with increased risk of metabolic syndrome [42]
2. Definition of Metabolic Syndrome [2,11]
   1. Defined as having at least 3 of the following 5 criteria:
   2. Abdominal Obesity: waist circumference (now adjusted for geography/ethnicity)
   3. Hypertriglyceridemia: triglycerides >149 mg/dL (>1.68 mmol/L)
   4. Low HDL: <40mg/dL (1.04 mmol/L) men, <50mg/dL (1.29 mmol/L) women
   5. High blood pressure: >130/85 mm Hg
   6. High fasting glucose: >109 mg/dL (>6.1 mmol/L)
   7. Insulin resistance is not required for syndrome
   8. Vascular inflammation is a key component (usually with elevated CRP)
   9. Having 2 criteria is "probable" metabolic syndrome
3. Waste Circumference [21]
   1. Worldwide definition now based on ethnic groups
   2. Europoids: >94cm men, >80cm women
   3. South Asians and Chinese: >90cm men, >80cm women
   4. Japanese: >85cm men, >90cm women
   5. Ethnic south and central Americans - use south Asian recommendations
   6. Sub-Saharan Africas - use European data
   7. Eastern Mediterranean and Middle East Arab populations - use European data
4. Complications of Metabolic Syndrome
   1. Overall prevalence of metabolic syndrome is 22% and is age dependent in USA
   2. Chronic intervention is critical to prevent progression to frank diabetes
   3. Associated with 2.5X-4X increase in cardiac events and mortality [12]
   4. Associated with 2-5X increased risk for chronic renal failure [13]
   5. Metabolic syndrome / IRS is a 4-11X increased risk for nonalcoholic fatty liver disease [24]
   6. Prediabetes occurs in obese youth with similar characteristics as metabolic syndrome [14]
   7. Nonalcoholic fatty liver is now considered part of metabolic syndrome
5. Compensatory Hyperinsulinemia
   1. Normal Glucose Tolerance
   2. Impaired Glucose Tolerance (IGT)
   3. Type II DM
   4. Usually associated with elevated HbA1c (associated with increased CV risk) [9]
6. Central Obesity
   1. Central obesity only is a risk factor for cardiovascular disease
   2. This type of obesity is characterized by an "android" or "apple" shape
   3. Peripherally distributed ("gynoid" or "pair" shape) is not a risk factor
7. Medications Associated with Hyperglycemia
   1. Glucocorticoids (Cushing Syndrome)
   2. Niacin
   3. Cyclosporine and Tacrolimus
   4. HIV Protease Inhibitors (see below)
   5. Sympathomimetics
8. Acute and Critical Illness [15]
   1. Hyperglycemia often present in acutely ill patients
   2. Many contributors including endogenous norepinephrine, glucocorticoids
   3. Various medications (above) and parenteral nutrition contribute
   4. Hyperglycemia is more detrimental to most acutely ill patients than hypoglycemia
   5. Therefore, hyperglycemia should be treated aggressively
   6. Close monitoring of plasma glucose is required, goal is average glucose 100mg/dL
   7. Insulin with glucose infusions are recommended to maintain 72-126mg/dL plasma glucose
9. HAIR-AN Syndrome [16]
   1. Hyperandrogenism
   2. Insulin resistance
   3. Acanthosis nigricans
   4. Rare disorder in women
   5. Antiandrogen therapy, weight loss, and normalizing glycemia are used
10. Other Very Rare Genetic Syndromes [6]
    1. Insulin receptor mutations - Leprechaun syndrome (see below)
    2. Insulin receptor blocking antibodies
    3. Altered insulin secretion (several monogenic disorders)
    4. These may be associated with acanthosis nigricans (hyperpigementation)

E. Atherosclerosis and the Metabolic Syndrome [17]

1. Mechanisms of Increased Atherosclerosis
   1. Dyslipidemia (mixed with hyprertriglyceridemia)
   2. Endothelial dysfunction
   3. Hypercoagulability including platelet hyperaggregability, impaired fibrinolysis
   4. Toxic effects of hyperglycemia including oxidative stress
   5. Autonomic neuropathy
   6. Chronic low grade inflammation likely contributes to insulin resistance and ß-cell failure [18] and to early atherosclerosis
   7. Pioglitazone 150-45mg/d for 18 months reduced carotid intima-media thickness compared with glimepiride 1-4mg/d [47]
2. Dyslipidemias
   1. Dyslipidemias are present in essentially all patients with any insulin resistance
   2. Hypertriglyceridemia with increased VLDL and reduced HDL are most common in DM 2
   3. Patients have hyperapolipoprotein B levels and increased small, dense LDL (LDL B)
   4. LDL B particles are highly atherogenic
   5. Low HDL is most important risk factor for premature CAD
   6. All of these lipid abnormalities are major contributors to premature atherosclerosis
   7. Elevated free fatty acids may reduce skeletal muscle sensitivity to insulin
   8. Also occurs with antiretroviral drugs, mainly protease inhibitors (see below)
3. Insulin and Lipid Markers
   1. Fasting mature insulin level elevation often occurs with elevated lipids
   2. Fasting insulin levels also found with increased Apolipoprotein B and small LDL levels
   3. Elevations in these three risk factors increases risk of ischemic heart diseases ~18 fold
   4. These markers appear more biologically relevant molecules than standard lipid tests
   5. Insulin elevations may be compensatory for abnormal lipid metabolism
4. Endothelial Dysfunction
   1. Prominant feature of the IRS
   2. HTN, hypercoagulability, dyslipidemias, hyperinsulinemia all affect endothelium
   3. Reduced nitric oxide levels
   4. Elevated levels of asymmetric dimethylarginine (ADMA) correlate with insulin resistance [19]
   5. ADMA is an inhibitor of nitric oxide synthetase and is associated with cardiovascular disease
   6. Elevated angiotensin II and endothelin activity
   7. Increased smooth muscle proliferation
   8. Increase in local inflammation contributing to atherosclerosis
   9. Increase in procoagulants is likely synergistic with endothelial dysfunction in increasing risk for coronary disease [20]
5. Insulin Response and Coagulopathy [20]
   1. Elevated insulin levels associated with increased plasminogen activator inhibitor (PAI-1)
   2. Insulin itself stimulates PAI-1 production and may contribute to thrombogenesis
   3. Hyperinsulinemia and insulin resistance lead to impaired fibrinolysis
   4. Mean levels of all hemostatic (procoagulant) factors increase with increasing fasting insulin levels, even in persons with normal glucose tolerance
   5. PAI-1 and tissue plasminogen activator levels increased with increasing insulin levels in patients with glucose intolerance
6. Other Associations
   1. Coronary Artery Disease (CAD)
   2. Microvascular Angina
   3. Polycystic Ovary Syndrome (PCOS)
   4. Late effects after bone marrow transplantation [22]
   5. Metabolic syndrome (IRS) with high inflammation contributes to cognitive decline [23]
   6. Exposure to higher chronic insulin levels associated with pancreatic cancer in men [31]

F. Evaluation

1. History and Physical for Associated Problems
   1. Hypertension
   2. Weight (and measurement of waist to hip ratio, WHR)
   3. Cardiovascular examination
   4. Frank Diabetes (Type 2 runs in families)
   5. Drug-induced hyperglycemia
2. Laboratory Measurements
   1. Serum glucose and glycosylated hemoglobin (fructosamine)
   2. Serum fasting total / LDL / HDL cholesterol and triglycerides
   3. Serum BUN, creatinine and uric acid
   4. Urine glucose, HbA1c, creatinine, and protein levels
   5. Electrocardiogram (ECG)
   6. Infrequently presents with frank diabetic ketoacidosis
   7. Serum level of retinol-binding protein 4 (RBP4) correlates with insulin resistance [4]
   8. RBP4 is an adipocyte hormone whose levels predict frank diabetes [4]
3. Common Laboratory Abnormalities [20]
   1. Hyperuricemia
   2. Increased Type I plasminogen activator inhibitor (PAI)
   3. Decreased plasminogen activator activity (may lead to hypercoagulability)
   4. Demonstrable endothelial cell dysfunction with reduced nitric oxide production
   5. Hyperglycemia
4. Liver and Hepatobiliary Disease [25]
   1. Nonalcoholic fatty liver - essentially metabolic syndrome and frank DM2 patients
   2. Cirrhosis
   3. Hepatocellular carcinoma
   4. Liver disease in IRS/DM often associated with Hepatitis C Virus (HCV) infection
5. Identification of Insulin Resistant Persons [27]
   1. Persons with fasting glucose in the top tertile after glucose administration
   2. Metabolic markers can identify obese (BMI >25kg/m2) persons with IRS
   3. Combining the following 3 markers leads to good identification of obese patients with IRS:
   4. Plasma triglyceride concentration
   5. Ratio of plasma triglycerides to HDL
   6. Serum insulin concentration

G. Treatment of IRS

1. Therapy Overview
   1. Weight loss
   2. Exercise program
   3. Dietary changes
   4. In obese patients with IRS, increased dairy intake may reduce DM 2 and cardiac risk [28]
   5. Weight reduction with BOTH caloric restriction AND excercise is preferred over either modality alone in terms of health and fitness [29]
   6. Combination of caloric restriction and exercise program reduced insulin resistance [29]
   7. Mediterranean diet reduces markers of metabolic syndrome and diabetes [30]
   8. Pharmacologic Therapy
2. Therapy Directed at Specific Abnormalities
   1. ACE inhibitors (ACE-I) are generally preferred for HTN
   2. ACE-I improve vascular endothelial dysfunction as well as HTN
   3. Angiotensin II receptor antagonists (ARB) may also be used
   4. Glitazones may be the most optimal agents for treating insulin resistance
   5. Glitazones have carbohydrate-independent positive effects on endothelium
   6. Aggressive lipid lowering therapy with HMG-CoA reductase inhibitors recommended
   7. Atorvastatin is the only statin with significant triglyceride reduction
   8. Fibrates (fenofibrate, gemfibrozil) also reduce triglyceride levels well
3. Normalization of Glucose
   1. Metformin is very effective alone and in combination with insulin or glyburide
   2. Metformin also induces weight loss (and prevents insulin induced weight gain)
   3. Both metformin and lifestyle modifications delay the onset of DM2 in patients with IRS [44]
   4. Lifestyle modifications more effective than metformin delaying DM2 in IRS patients [44]
   5. Glitazones has beneficial effects on lipids and other metabolic parameters
   6. Glitazones are effective in polycystic ovary syndrome, can improve fertility
   7. Troglitazone is off the market, but pioglitazone and rosiglitazone are as effective [32]
   8. Acarbose reduces onset of DM2 and car
4. Nonhypoglycemic Effects of Glitazones [33]
   1. Reduction of blood pressure
   2. Reduction of triglycerides and increase HDL (and also LDL) levels
   3. Improvement in fibrinolysis: decrease PAI-1 and fibrinogen levels
   4. Decrease in carotid artery intima-media thickness
   5. Increase LDL levels but increase LDL particle size and reduce LDL oxidation
   6. Reduce microalbuminuria
   7. Induce coronary artery relaxation, improve stroke volume and cardiac index
5. Acarbose 100mg tid reduces risk of developing frank DM2 ~25% [34] and reduces incidence of hypertension and cardiovascular disease [43] in persons with IGT
6. Dehydroepiandrosterone (DHEA) 50mg qd in elderly persons reduced subcutaneous and visceral fat, reduced insulin levels, and improved glucose handling [35]
7. Rimonabant [45]
   1. Selective cannabanoid 1 receptor antagonist
   2. Central action: Increases satiety and reduces food intake
   3. Effects on GI tract to reduce food intake
   4. Effects on adipose tissue to improve metabolic syndrome parameters
   5. In obese patients, 20mg po qd reduced weight by 6.6kg versus control in 1 year
   6. Improvements in HDL-cholesterol, triglycerides, insulin resistance, metabolic syndrome
   7. Generally well tolerated

H. Hypertension and Insulin Resistance

1. ~40% of persons with hypertension have IGT
2. In addition, these patients often have hyperinsulinemia [20]
   1. Traditional cardiac risk factors explain only ~50% of CAD in diabetics
   2. Additional risk factors including insulin resistance also appear to play a role
   3. Hyperinsulinemia is also a risk factor for coronary artery disease
   4. High triglycerides and low HDL cholesterol are associated with hyperinsulinemia
3. Ingestion of food (mainly fat and carbohydrates) stimulates the sympathetic system
   1. Chronic hyperinsulinemia stimulates the sympathetic system (norepinephrine)
   2. This appears to be true in obese and non-obese persons
   3. Somatostatin inhibits insulin synthesis, reducing sympathetic tone and blood pressure
4. Nitrendipine was safe and effective in elderly diabetics with systolic HTN [36]
5. Thiazide diuretics and ß-adrenergic blockers may exacerbate insulin resistance [37]

I. Drug-Induced Hyperglycemia [37]

1. Thiazide Diuretics
   1. Associated with reduction in total body potassium (K+)
   2. Reduced body K+ leads to decreased insulin secretion
   3. Effects reduced by K+ replacement or combination with K+ sparing diuretic
2. ß-Adrenergic Blockers
   1. May reduce pancreatic insulin release
   2. Highly variable effects
   3. Nonselective and some ß1-selective agents are implicated
   4. Carvidilol appears to increase insulin sensitivity and improve glucose control
3. Atypical Antipsychotics
   1. Olanzapine, clozapine, risperidone, quetiapine
   2. Often associated with significant weight-gain
   3. Appear to cause insulin resistance
   4. Over 5 years on clozapine, incidence of Type 2 DM was 30%
4. Isotretinoin (cis-13-retinoic acid)
   1. Synthetic vitamin A derivative for severe acne
   2. Increased risk of lipid anomalies (high LDL, hypertriglyceridemia, low HDL), IRS
   3. Patients with initial >89 mg/dL increase in triglycerides are at highest risk for developing hyperlipidemia and insulin resistance syndromes [38]
5. Protease Inhibitors (see below)

J. HIV (Protease Inhibitor) Associated Lipodystrophy [37,39]

1. Characteristics of the Syndrome
   1. Wasting of peripheral fat
   2. Accumulation of fat in dorsocervical area ("buffalo hump")
   3. Accumulation of fat in breasts and inside the abdominal cavity
   4. Hyperlipidemia and insulin resistance occur
   5. Protease inhibitors (PI) are usually implicated
   6. However, lipodystrophy can occur in HIV+ persons who have not taken PI
   7. Other non-PI antiretroviral drugs contribute or can cause the lipodystrophy
2. Metabolic Features
   1. Hypertriglyceridemia
   2. Hypercholesterolemia
   3. Insulin resistance (hyperinsulinemia, elevated C-peptide)
   4. Type 2 Diabetes Mellitus
3. Proposed Pathophysiology of Syndrome [40]
   1. Adipocyte generation requires specific transcription factors
   2. Three critical factors: C/EBPß, PPARg, C/EBP alpha
   3. Differentiation of adipocytes enhanced by SREBP1 which activates PPARg
   4. SREBP1 is sterol regulatory element binding protein 1
   5. Antiretrovirals, particularly PI, alter SREBP1 function and lead to reduced PPARg
   6. Glitazones, which activates PPARg, may be effective in this syndrome [46]
   7. May also represent an autonomic neuropathy controlled by central nervous system [41]
4. Clinical Characteristics
   1. PI's may cause hyperglycemia and frank diabetes occurs in ~5%
   2. PI's are associated with lipodistrophy, hyperlipidemia and diabetes
   3. Lipodystrophy (atrophy of fat) occurs in up to 83% of patients treated with PI's
   4. Central adiposity also occurs and is likely related to insulin resistance
   5. Diagnosis can be made by observation and measurement of elevated insulin C-peptide
   6. Demonstration of glucose intolerance with oral glucose loading can also be done

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