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Definition of Diabetes
Diabetes is any disorder characterized by excessive urine excretion. The most common form of diabetes is diabetes mellitus, a metabolic disorder in which there is an inability to oxidize carbohydrate due to disturbances in insulin function. Diabetes mellitus is characterized by elevated glucose in the plasma and episodic ketoacidosis. Additional symptoms of diabetes mellitus include excessive thirst, glucosuria, polyuria, lipemia and hunger. If left untreated the disease can lead to fatal ketoacidosis. Other forms of diabetes include diabetes insipidus and brittle diabetes. Diabetes insipidus is the result of a deficiency of antidiuretic hormone. The major symptom of diabetes insipidus (excessive urine output) results from an inability of the kidneys to resorb water. Brittle diabetes is a form that is very difficult to control. It is characterized by unexplained oscillations between hypoglycemia and acidosis.
Criteria, which clinically establish an individual as suffering from diabetes mellitus, include:
1. having a fasting plasma glucose level in excess of 126mg/dL (7mmol/L). Normal levels should be less than 100mg/dL (5.6mmol/L) or:
2. having plasma glucose levels in excess of 200mg/dL (11mmol/L) at two times points during an oral glucose tolerance test, OGTT, one of which must be within 2 hrs of ingestion of glucose.
The earlier a person is diagnosed with diabetes (principally type 2) the better chance the person has of staving off the primary negative consequences which are renal failure, blindness and limb amputations due to circulatory problems. The American Diabetes Association is planning to recommend that physicians consider patients to be pre-diabetic if their fasting blood glucose level is above 100mg/dL but less than 125mg/dL and whose glucose levels are at least 140mg/dL but less than 200mg/dL following an oral glucose tolerance test (OGTT).
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Glucose tolerance curve for a normal person and one with non-insulin-dependent diabetes mellitus (NIDDM, Type 2 diabetes). The dotted lines indicate the range of glucose concentration expected in a normal individual. |
Types of Diabetes Mellitus
Diabetes mellitus is a heterogeneous clinical disorder with numerous causes. Two main classifications of diabetes mellitus exist, idiopathic and secondary.
Idiopathic diabetes is divided into two main types; insulin dependent and non-insulin-dependent. Insulin-dependent diabetes mellitus, IDDM (more commonly referred to as type 1 diabetes) is defined by the development of ketoacidosis in the absence of insulin therapy. See the Diabetic Ketoacidosis diagnosis and treatment page. Type 1 diabetes most often manifests in childhood (hence, also called juvenile onset diabetes) and is the result of an autoimmune destruction of the β-cells of the pancreas. Non-insulin-dependent diabetes mellitus, NIDDM (more commonly referred to as type 2 diabetes) is characterized by persistent hyperglycemia but rarely leads to ketoacidosis. Type 2 diabetes generally manifests after age 40 and therefore has the obsolete name of adult onset-type diabetes. Type 2 diabetes can result from genetics defects that cause both insulin resistance and insulin deficiency. There are two main forms of type 2 diabetes:
1. Late onset associated with obesity.
2. Late onset not associated with obesity.
There is a strong correlation between obesity and the onset of type 2 diabetes with its associated insulin resistance. It should be pointed out that in the United States the proportion of the population under 40 that can be clinically defined as obese now exceeds 25%. Many children are obese and are developing type 2 diabetes at an alarming epidemic rate. The dramatic rise in obesity in the US has lead to an equally alarming increase in the percentage of the population who suffer from the metabolic syndrome. The metabolic syndrome is a clustering of atherosclerotic cardiovascular disease risk factors, one of which involves insulin resistance characteristic in type 2 diabetes. It should be pointed out that obesity alone does not always lead to insulin resistance as some individuals who are obese do not experience insulin resistance and conversely, some individuals who manifest insulin resistance are not obese. These latter observations point to the added role of genetics in the acquisition of insulin resistance.
Secondary, or other specific types of diabetes mellitus are the result of many causes including:
1. Maturity onset type diabetes of the young (MODY) was previously considered to be a third form of type 2 diabetes. However, with the discovery of specific mutations leading to MODY, it is now classified under secondary or other specific types of diabetes. MODY is characterized by onset prior to age 25. All cases to date have shown impaired β-cell function. Patients may also exhibit insulin resistance and late β-cell failure. Evidence indicates that mutations in 10-12 different genes have been correlated with the development of MODY. Mutations in the 6 genes described here are all clearly correlated to MODY:
MODY1: the transcription factor identified as hepatic nuclear factor-4α (HNF-4α).MODY2: pancreatic glucokinase
MODY3: the transcription factor HNF-1α. This gene is also called hepatocyte transcription factor-1 (TCF1).
MODY4: the homeodomain transcription factor insulin promoter factor-1 (IPF-1). This gene is more commonly called PDX1 derived from pancreas duodenum homeobox-1.
MODY5: the transcription factor HNF-1β. This gene is also called hepatocyte transcription factor-2 (TCF2).
MODY6: the bHLH transcription factor NeuroD1. NeuroD1 was first identified as a neural fate-inducing gene. The hamster β2 gene, shown to regulate insulin transcription is identical to NeuroD1 so the gene is often called NeuroD/β2.
2. Pancreatic disease: Pancreatectomy leads to the clearest example of secondary diabetes. Cystic fibrosis and pancreatitis can also lead to destruction of the pancreas.
3. Endocrine disease: Some tumors can produce counter-regulatory hormones that oppose the action of insulin or inhibit insulin secretion. These counter-regulatory hormones are glucagon, epinephrine, growth hormone and cortisol.
a. Glucagonomas are pancreatic cancers that secrete glucagon.
b. Pheochromocytomas secrete epinephrine.
c. Cushing syndrome results in excess cortisol secretion.
d. Acromegaly results in excess growth hormone production.
4. Drug-induced diabetes; treatment with glucocorticoids and diuretics can interfere with insulin function.
5. Anti-insulin receptor autoantibodies (Type B insulin resistance).
6. Mutations in the insulin gene.
7. Mutations in insulin receptor gene which lead to the syndromes listed below. Two clinical features are common in all syndromes that result from mutations in the insulin receptor gene: acanthosis nigricans and hyperandrogenism (the latter being observed only in females).
a. Leprachaunism
c. Type A insulin resistance
8. Gestational diabetes; this syndrome sets in during pregnancy and usually resolves itself following childbirth.
9. Many other genetic syndromes have
either diabetes or impaired glucose tolerance associated with them; lipoatrophic
diabetes, Wolfram
syndrome, Down syndrome,
Klinefelter syndrome (XXY males), Turner
syndrome, myotonic
dystrophy, muscular
dystrophy, Huntington
disease, Friedrich
ataxia (associated with deficiency in purine nucleotide phosphorylase), Prader-Willi
syndrome, Werner
syndrome, Cockayne
syndrome, and others such as those indicated above in 2 and 6.
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Insulin-Dependent Diabetes Mellitus (IDDM) Type 1
Etiology of Type 1 Diabetes
Type 1 diabetes has been shown to be the result of an autoimmune reaction to antigens of the islet cells of the pancreas. There is a strong association between IDDM and other endocrine autoimmunities (e.g. Addison disease). Additionally, there is an increased prevalence of autoimmune disease in family members of IDDM patients.
Types of Autoantibodies
1. Islet cell cytoplasmic antibodies: The primary antibodies found in 90% of type 1 diabetics are against islet cell cytoplasmic proteins (termed ICCA, islet cell cytoplasmic antibodies). In non-diabetics ICCA frequency is only 0.5% - 4%. The presence of ICCA is a highly accurate predictor of future development of IDDM. ICCA are not specific for the β-cells and recognize antigens in other cell types in the islet. However, the autoimmune attack appears to selectively destroy β-cells. Therefore, the antibodies may play a primary role in the destruction of islet cells. It is an equally likely possibility that the production of anti-islet antibodies occurs as a result of the destruction of β-cells. Whether a direct cause or an effect of islet cell destruction, the titer of the ICCA tends to decline over time.
2. Islet cell surface antibodies: Autoantibodies directed against cell-surface antigens (ICSA) have also been described in as many as 80% of type 1 diabetics. Similar to ICCA, the titer of ICSA declines over time. Some patients with type 2 diabetes have been identified that are ICSA positive.
3. Specific antigenic targets of islet cells: Antibodies to glutamic acid decarboxylase (GAD) have been identified in over 80% of patients newly diagnosed with IDDM. Like ICCA, anti-GAD antibodies decline over time in type 1 diabetics. The presence of anti-GAD antibodies is a strong predictor of the future development of IDDM in high-risk populations. Anti-insulin antibodies (IAA) have been identified in IDDM patients and in relatives at risk to develop IDDM. These IAA are detectable even before the onset of insulin therapy in type 1 diabetics. IAA are detectable in around 40% of young children with IDDM.
Pathophysiology of Type 1 Diabetes
The autoimmune destruction of pancreatic β-cells leads to a deficiency of insulin secretion. It is this loss of insulin secretion that leads to the metabolic derangements associated with IDDM. In addition to the loss of insulin secretion, the function of pancreatic α-cells is also abnormal. There is excessive secretion of glucagon in IDDM patients. Normally, hyperglycemia leads to reduced glucagon secretion. However, in patients with IDDM, glucagon secretion is not suppressed by hyperglycemia. The resultant inappropriately elevated glucagon levels exacerbates the metabolic defects due to insulin deficiency (see below). The most pronounced example of this metabolic disruption is that patients with IDDM rapidly develop diabetic ketoacidosis in the absence of insulin administration. If somatostatin is administered to suppress glucagon secretion, there is a concomitant suppression in the rise of glucose and ketone bodies. Particularly problematic for long term IDDM patients is an impaired ability to secrete glucagon in response to hypoglycemia. This leads to potentially fatal hypoglycemia in response to insulin treatment in these patients.
Although insulin deficiency is the primary defect in IDDM, in patients with poorly controlled IDDM there is also a defect in the ability of target tissues to respond to the administration of insulin. There are multiple biochemical mechanisms that account for this impairment of tissues to respond to insulin. Deficiency in insulin leads to elevated levels of free fatty acids in the plasma as a result of uncontrolled lipolysis in adipose tissue. Free fatty acids suppress glucose metabolism in peripheral tissues such as skeletal muscle. This impairs the action of insulin in these tissues, i.e. the promotion of glucose utilization. Additionally, insulin deficiency decreases the expression of a number of genes necessary for target tissues to respond normally to insulin such as glucokinase in liver and the GLUT 4 class of glucose transporters in adipose tissue. The major metabolic derangements which result from insulin deficiency in IDDM are impaired glucose, lipid and protein metabolism.
Glucose Metabolism: Uncontrolled IDDM leads to increased hepatic glucose output. First, liver glycogen stores are mobilized then hepatic gluconeogenesis is used to produce glucose. Insulin deficiency also impairs non-hepatic tissue utilization of glucose. In particular in adipose tissue and skeletal muscle, insulin stimulates glucose uptake. This is accomplished by insulin-mediated movement of glucose transporter proteins to the plasma membrane of these tissues. Reduced glucose uptake by peripheral tissues in turn leads to a reduced rate of glucose metabolism. In addition, the level of hepatic glucokinase is regulated by insulin. Therefore, a reduced rate of glucose phosphorylation in hepatocytes leads to increased delivery to the blood. Other enzymes involved in anabolic metabolism of glucose are affected by insulin (primarily through covalent modifications). The combination of increased hepatic glucose production and reduced peripheral tissues metabolism leads to elevated plasma glucose levels. When the capacity of the kidneys to absorb glucose is surpassed, glucosuria ensues. Glucose is an osmotic diuretic and an increase in renal loss of glucose is accompanied by loss of water and electrolytes, termed polyuria. The result of the loss of water (and overall volume) leads to the activation of the thirst mechanism (polydipsia). The negative caloric balance which results from the glucosuria and tissue catabolism leads to an increase in appetite and food intake (polyphagia).
Lipid Metabolism: One major role of insulin is to stimulate the storage of food energy following the consumption of a meal. This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates hepatocytes to synthesize triglycerides and storage of triglycerides in adipose tissue. In opposition to increased adipocyte storage of triglycerides is insulin-mediated inhibition of lipolysis. In uncontrolled IDDM there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. Free fatty acids are also taken up by the liver.
Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibit carnitine palmitoyltransferase I, the enzyme required for the transport of fatty acyl-CoA's into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA's into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle. However, in hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, acetoacetate and β-hydroxybutyrate. These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the organisms ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.
Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL), an enzyme on the surface of the endothelial cells lining the vessels. In particular, LPL activity allows fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hypertriglyceridemia results.
Protein
Metabolism: Insulin
regulates the synthesis of many genes, either positively or negatively that
then affect overall metabolism. Insulin has a global effect on protein
metabolism, increasing the rate of protein synthesis and decreasing the rate
of protein degradation. Thus, insulin deficiency will lead to increased
catabolism of protein. The increased rate of proteolysis leads to elevated
concentrations in plasma amino acids. These amino acids serve as precursors for
hepatic and renal gluconeogensis. In liver, the increased gluconeogenesis
further contributes to the hyperglycemia seen in IDDM.
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Non-Insulin-Dependent Diabetes Mellitus (NIDDM): Type 2
Etiology of Type 2 Diabetes
NIDDM is characterized by a lack of the need for insulin to prevent ketoacidosis. Type 2 diabetes refers to the common form of idiopathic NIDDM. NIDDM is not an autoimmune disorder, however, there is a strong genetic correlation to the susceptibility to NIDDM. The susceptibility genes that predispose one to NIDDM have not been identified in most patients. This is due in part to the heterogeneity of the genes responsible for the susceptibility to NIDDM. Obesity is a major risk factor that predisposes one to NIDDM. Genetic studies in mice and rats have demonstrated a link between genes responsible for obesity and those that cause diabetes mellitus.
Pathophysiology of Type 2 Diabetes
Unlike patients with IDDM, those with NIDDM have detectable levels of circulating insulin. On the basis of oral glucose tolerance testing the essential elements of NIDDM can be divided into 4 distinct groups; those with normal glucose tolerance, chemical diabetes (called impaired glucose tolerance), diabetes with minimal fasting hyperglycemia (fasting plasma glucose <140 mg/dL), and diabetes mellitus in association with overt fasting hyperglycemia (fasting plasma glucose >140 mg/dL). In patients with the highest levels of plasma insulin (impaired glucose tolerance group) there was also elevated plasma glucose. This indicates that these individuals are resistant to the action of insulin. In the progression from impaired glucose tolerance to diabetes mellitus the level of insulin declines indicating that patients with NIDDM have decreased insulin secretion.
Additional studies have subsequently demonstrated that both insulin resistance and insulin deficiency is common in the average NIDDM patient. Many experts conclude that insulin resistance is the primary cause of NIDDM, however, others contend that insulin deficiency is the primary cause because a moderate degree of insulin resistance is not sufficient to cause NIDDM. As indicated above, most patients with the common form of NIDDM have both defects.
A number of candidate genes have been screened for having causative roles in type 2 diabetes. Although several monogenic loci are associated with type 2 diabetes (see MODY descriptions above) none has been shown to be a significant cause of the disease (i.e. >50% in all cases). Several of the genes having roles in progression to type 2 diabetes include pancreatic glucokinase (MODY 2), GLUT-2 (glucose transporter), glucagon receptor, glucagon-like protein-1 (GLIP-1), glucokinase regulatory protein and hexokinase-1.
Recent evidence has demonstrated a role for a member of the nuclear hormone receptor superfamily of proteins in the etiology of type 2 diabetes. A relatively new class of drugs used to increase the sensitivity of the body to insulin are the thiazolidinedione drugs (see below). These compounds bind to and alter the function of the peroxisome proliferator-activated receptor-γ, PPARγ. PPARγ is also a transcription factor and, when activated, binds to another transcription factor known as the retinoid X receptor, RXR. When these two proteins are complexed a specific set of genes becomes activated. PPARγ is a key regulator of adipocyte differentiation; it can induce the differentiation of fibroblasts or other undifferentiated cells into mature fat cells. PPARγ is also involved in the synthesis of biologically active compounds from vascular endothelial cells and immune cells.
Mutations in the gene for PPARγ have been correlated with insulin
resistance. It is still not completely clear how impaired PPARγ signaling can affect the sensitivity
of the body to insulin or indeed if the observed mutations are a direct or indirect
cause of the symptoms of insulin resistance.
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Genetics of Type 2 Diabetes
Development of type 2 diabetes is the result of multifactorial influences that include lifestyle, environment and genetics. The disease arises when insulin resistance-induced compensatory insulin secretion is exhausted. A high-caloric diet coupled with a sedentary lifestyle are the major contributing factors in the development of the insulin resistance and pancreatic β-cell dysfunction. However, a predisposing genetic background has long been suspected in playing a contributing role in the development of type 2 diabetes. By using whole-genome linkage analysis the entire genome of affected family members can be scanned and the family members monitored over several generations. In addition, large numbers of affected sibling-pairs can also be studied. Using these genome-wide linkage methods the first genes with polymorphisms to be identified with a correlation to type 2 diabetes susceptibility were calpain 10 (CAPN10) and hepatocyte nuclear factor 4-α (HNF4A). Note that HNF4A is also known to be associated with the development of MODY1 (see above).
CAPN10 is a calcium-activated neutral protease. Variation in the non-coding region of the CAPN10 gene is associated with a threefold increased risk of type 2 diabetes in Mexican Americans. However, in European populations polymorphisms in CAPN10 are less contributory to type 2 diabetes than other recently discovered genes. Genetic variants in CAPN10 may alter insulin secretion, insulin action as well as the production of glucose by the liver. Recent studies indicate that CAPN10 may have a critical role in the survival of pancreatic β-cells.
The hepatocyte nuclear factor family of proteins was first identified as an abundant class of transcription factors in the liver. In addition to the liver, HNF4A is expressed in pancreatic β-cells, kidneys and intestines. As indicated above, mutations in HNF4A can cause MODY1 which is characterized by a normal response to insulin but an impaired insulin secretory response in the presence of glucose. The HNF4A gene maps to a region of chromosome 20 that has been linked to type 2 diabetes. In addition to the mutations causing MODY1, single nucleotide polymorphisms (SNPs) in the HNF4A gene have an impact on pancreatic b-cell function leading to altered insulin secretion. The SNPs in the HNF4A gene that are related to development of type 2 diabetes lie in a promoter element called P2. The P2 promoter is used primarily in pancreatic cells, whereas, both the P1 and P2 promoters are used in liver cells.
Recent genome-wide screens for polymorphisms in type 2 diabetes have identified several new candidate genes. These include hematopoietically expressed homeobox (HHEX), solute carrier family 30 [zinc transporter], member 8 (SLC30A8), transcription factor 7-like 2 [T-cell specific HMG-box] (TCF7L2), potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11), peroxisome proliferator-activated receptor-γ (PPARG), cyclin-dependent kinase inhibitor 2B (CDKN2B), cyclin-dependent kinase-5 [CDK5] subunit associated protein 1-like 1 (CDKAL1) and insulin-like growth factor binding protein 2 (IGFBP2).
It is not the aim of this section to review the function of all of these
genes nor to detail the potential for polymorphism in the genes to
contribute to the development of type 2 diabetes. However, two of these
genes have been discussed on this page. The function of KCNJ11 is described
in the Insulin Action page. The function of PPARG and its
association with inherited forms of type 2 diabetes was discussed in
the above section and details of targeting this gene product in the
treatment of the hyperglycemia associated with type 2 diabetes is presented
below under Therapeutic Intervention.
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Diabetes and The "Metabolic Syndrome"
Although the metabolic syndrome (also called syndrome X) is not exclusively associated with type 2 diabetes and the associated insulin resistance, the increasing prevalence of obesity and associated development of type 2 diabetes places insulin resistance as a major contributor to the syndrome. The metabolic syndrome is defined as a clustering of atherosclerotic cardiovascular disease risk factors that include visceral adiposity (obesity), insulin resistance, low levels of HDLs and a systemic proinflammatory state. There are key components to the metabolic syndrome which include hypertension, dyslipidemia, insulin resistance, chronic inflammation, impaired fibrinolysis, procoagulation and most telling central obesity.
The role of adipose tissue (fat) stems from the fact that the organ is active at secretion of cytokines, termed adipocytokines. These include tumor necrosis factor-α (TNFα), interleukin-6 (IL-6), leptin, adiponectin and resistin. Leptin has received particular attention of late due to its role in obesity in addition to the fact that recent data indicates that plasma leptin levels are found to be predictive of the potential for cardiovascular pathology.
Many clinicians and researchers believe that insulin resistance underlies the cardiovascular pathologies of the metabolic syndrome. One primary reason for this is the role of insulin in fat homeostasis. As indicated above, the major role of insulin is to induce the storage of fuel. This can be as fat (triacylglycerides, TGs) in adipose tissue or as carbohydrate in the form of glycogen in liver and skeletal muscle. The effect of insulin resistance at the level of fat homeostasis is an increase in circulating TGs, referred to as dyslipidemia. Due to insulin resistance there is an increase in the delivery of peripheral fatty acids to the liver which in turn drives hepatic TG synthesis. These TGs are then packaged into lipoprotein particles termed VLDLs (very low density lipoproteins) which are returned to the circulation.
Taken together, the insulin resistance and its associated negative effects on metabolism, the increased levels of circulating TGs, the reduced levels of HDLs and hypertension, all contribute to the progression of atherosclerosis. With associated coagulation and fibrinolysis pathologies, the cardiovascular events of the metabolic syndrome can be devastating.
Since
many of these pathologies can be reversed with proper diet and exercise, it is
in a persons’ best interest to take responsibility for the role their
life style choices play in the development of the metabolic syndrome.
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Therapeutic Intervention for Hyperglycemia
Many, if not all, of the vascular consequences of insulin resistance are due to the persistent hyperglycemia seen in type 2 diabetes. For this reason a major goal of therapeutic intervention in type 2 diabetes is to reduce circulating glucose levels. There are many pharmacologic strategies to accomplish these goals.
1. The α-Glucosidase inhibitors: α-glucosidase inhibitors such as acarbose (Precose®) and miglitol (Glyset®) function by interfering with the action of the α-glucosidases present in the small intestinal brush border. The consequence of this inhibition is a reduction in digestion and the consequent absorption of glucose into the systemic circulation. The reduction in glucose uptake allows the pancreatic β-cells to more effectively regulate insulin secretion. The advantage to the use of the α-glucosidase inhibitors is that they function locally in the intestine and have no major systemic action. Hypoglycemia does not usually occur with the use of α-glucosidase inhibitors but they are effective at reducing fasting plasma glucose (FPG) levels and levels of glycosylated hemoglobin (HbA1c). The common adverse side effects of these inhibitors are abdominal bloating and discomfort, diarrhea and flatulence.
2. The Sulfonylureas: The sulfonylurea and meglitinide classes of oral hypoglycemic drugs are referred to as endogenous insulin secretagogues because they induce the pancreatic release of endogenous insulin.
The sulfonylureas have been used in the US for nearly 50 years. The first generation sulfonylureas (tolbutamide, acetohexamide, chlorpropramide and tolazamide) are not routinely prescribed any longer in the US. The second generation sulfonylureas include glipizide (Glucotrol®), glimepiride (Amaryl®) and glyburide (DiaBeta®, Micronase®, Glynase®). Because all of these drugs can induce pronounced hypoglycemia, treatment is initiated with the lowest possible dose and carefully monitored until the dose is found that results in a FPG of 110-140mg/dL. Sulfonylureas function by binding to and inhibiting the pancreatic ATP-dependent potassium channel that is normally involved in glucose-mediated insulin secretion (see above under insulin function). Sulfonylureas have no significant effects on circulating triglycerides, lipoproteins or cholesterol.
3. The Meglitinides: As indicated, the meglitinides repaglinide (Prandin®) and nateglinide (Starlix®) are non-sulfonylurea insulin secretagogues that are both fast acting and of short duration. Like the sulfonylureas, meglitinides therapy results in significant reduction in FPG as well as HbA1c. The mechanism of action of the meglitinides is initiated by binding to a receptor on the pancreatic β-cell that is distinct from the receptors for the sulfonylureas. However, meglitinides do exert effects on potassium conductance. Like the sulfonylureas, the meglitinides have no direct effects on the circulating levels of plasma lipids.
4. The Biguanides: The biguanides are a class of drugs that function to lower serum glucose levels by enhancing insulin-mediated suppression of hepatic glucose production and enhancing insulin-stimulated glucose uptake by skeletal muscle. Metformin (Glucophage®) is a member of this class and is currently the most widely prescribed insulin-sensitizing drug in current clinical use. Metformin administration does not lead to increased insulin release from the pancreas and as such the risk of hypoglycemia is minimal. Because the major site of action for metformin is the liver its use can be contraindicated in patients with liver dysfunction. The drug is ideal for obese patients and for younger type 2 diabetics.
Evidence on the mode of action of metformin shows that it improves insulin sensitivity by increasing insulin receptor tyrosine kinase activity, enhancing glycogen synthesis and increasing recruitment and transport of GLUT4 transporters to the plasma membrane. Additionally, it has been shown that metformin affects mitochondrial activities dependent upon the model system studied. Metformin has a mild inhibitory effect on complex I of oxidative phosphorylation, has antioxidant properties, and activates both glucose 6-phosphate dehydrogenase, G6PDH and AMP-activated protein kinase, AMPK. The importance of AMPK in the actions of metformin stems from the role of AMPK in the regulation of both lipid and carbohydrate metabolism (see AMPK: Master Metabolic Regulator for more details). In adipose tissue, metformin inhibits lipolysis while enhancing re-esterification of fatty acids.
In adolescent females with type 2 diabetes, the use of metformin is highly recommended to reduce the incidence as well as the potential for polycystic ovarian syndrome, PCOS. PCOS is brought on by the hyperinsulinemia of type 2 diabetes. Insulin effects on the ovary drive conversion of progesterone to testosterone and a reduction in serum hormone binding globulin (SHBG). Taken together, the effects of hyperinsulinemia lead to a hyperandrogenic state in the ovary resulting in follicular atresis and ovulatory dysfunction.
5. The Thiazolidinediones (TZDs): The TZDs, such as troglitazone (Rezulin®: Warner Lambert Co. but this drug was voluntarily removed from the market in 2000), rosiglitazone (Avandia®: GlaxoSmithKline) and pioglitazone (Actos®: Eli Lilly and Co.) have been proven useful in treating the hyperglycemia associated with insulin-resistance in both type 2 diabetes and non-diabetic conditions. The TZDs function as agonists for the transcription factor, PPARγ. PPARγ is a member of a superfamily of transcription factors that also include the closely related members, PPARα and PPARδ. PPARγ exists as a heterodimer with the nuclear retinoid X receptors, RXRs. The heterodimer binds to PPAR response elements (PPREs) in a number of target genes. Without ligand bound the heterodimer is associated with a co-repressor complex that includes a histone deacetylase. Deacetylated histone keeps DNA in a transcriptionally repressed state. When ligand binds to PPARγ the co-repressor complex dissociates and a co-activator complex containing histone acetylase associates resulting chromatin structural changes and transcriptional activation. The net effect of the TZDs is a potentiation of the actions of insulin in liver, adipose tissue and skeletal muscle, increased peripheral glucose disposal and a decrease in glucose output by the liver. Genes shown to be affected by PPARγ action include those encoding glucokinase, GLUT4, malic enzyme, lipoprotein lipase, fatty acyl-CoA synthase and adipocyte fatty acid binding protein. Given that PPARγ is predominantly expressed in adipose tissue, the effects of PPARγ agonists seen in the liver and skeletal muscle may be exerted via endocrine signaling from adipocytes. Recently it was shown that mutations in the PPARγ gene were correlated to familial insulin resistance.
6. Targeting glucagon-like peptide-1 (GLP-1): The synthesis and activities associated with GLP-1 were discussed above. As review, the primary metabolic responses to GLP-1 release from the enteroendocrine L-cells of the gut are inhibition of glucagon secretion and enhancement of glucose-dependent insulin release from the pancreas, both effects lead to decreased glycemic excursion. As indicated above, the hormonal action of GLP-1 is rapidly terminated as a consequence of enzymatic cleavage by DPP IV. Recent clinical evidence has shown that either infusion of GLP-1 or inhibition of DPP IV can result in dramatic reductions in plasma glucose concentrations, reductions in HbA1c and improvement in pancreatic β-cell function. Thus, both represent potential targets for the prevention of the hyperglycemia associated with diabetes and impaired insulin function (see the DPP IV review site maintained by Dr. Daniel J. Drucker).
There are advantages and disadvantages with the current therapeutic approaches to targeting GLP-1 action in diabetic patients. Current use of GLP-1 mimetics and/or GLP-1 receptor (GLP-1R) agonists focus on peptides or modified peptides and these must be injected. The need for chronic injection as a means of therapy always runs into the problem of patient compliance. One of the most promising GLP-1R agonists that has recently been approved for use is βYETTA® developed by Amylin Pharmaceuticals and Eli Lilly and Co.(also written as BYETTA). βYETTA® is composed of exenatide which is the lizard salivary peptide called exendin-4. Exenatide is 53% identical to GLP-1 at the level of amino acids and binds to and activates the GLP-1R. The advantage of exenatide as a therapeutic is that it is resistant to cleavage and inactivation by DPP IV. In a recent trial in patients with type 2 diabetes, βYETTA was shown not only to lower blood glucose levels and HbA1c, but patients also had an associated weight loss. Another promising GLP-1R agonist is liraglutide. This compound is a fatty acid-linked derivative of GLP-1 that is resistant to DPP IV cleavage.
Although targeting compounds that can inhibit the enzymatic action of DPP IV would seem like ideal candidates for treating the hyperglycemia of uncontrolled diabetes, there are several unknowns associated with DPP IV inhibition. One of these issues is the fact that GLP-1 and GIP are only two of the many known substrates for DPP IV cleavage. Thus, prolonged inhibition of DPP IV enzymatic activity may have unexpected consequences unrelated to control of hyperglycemia. Despite the potential for as yet unknown effects, the DDP IV inhibitor developed by Merck, Januvia® (sitagliptin), has recently been approved for use alone or in combination with either metformin or the thiazolidinediones. Treatment of patients with Januvia® as the only therapeutic agent for 18 weeks produced significant reductions of HbA1c, along with an improvement of β-cell function and no change in body weight.
DPP IV was originally identified as the lymphocyte cell surface antigen CD26. In humans CD26 functions in many pathways that are not directly related to its peptidase activity. It harbors adenosine deaminase-binding (ADA) properties and is involved in extracellular matrix binding. Of importance to the immune system, CD26 expression and activity are enhanced upon T-cell activation. CD26 interacts with other lymphocyte cell surface antigens including ADA, CD45 and the chemokine receptor CXCR4 (notable is the fact that CXCR4 is a T-cell attachment site for HIV). As yet it has not been clearly delineated as to whether the enzymatic activity of DPP IV is essential for the T-cell activating and co-stimulatory functions assigned to CD26. This issue must be resolved before chronic administration of DPP IV inhibitors can be applied in the clinic. Of significance, however, is that in gene knock-out mice lacking CD26 there is enhanced insulin secretion and improved glucose tolerance.
The major clinical advantages to the
use of DPP IV inhibitors is that the ones in current trials are orally
delivered. Compliance in patients is much higher with orally delivered drugs
than with those that require injection. The drug NVPDPP728 was shown to have
significant DPP IV inhibitory action and led to significant lowering of blood
glucose and HbA1c levels in type 2 diabetics. A second generation
DPP IV inhibitor LAF237 is currently in clinical trials.
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Biochemistry Page
Michael W. King, Ph.D / IU School of Medicine / miking at iupui.edu