Anti-Diabetic Drugs

Diabetes Mellitus • The incidence of diabetes is increasing at an alarming

rate in the US.

• Insulin – β cells secrete due to

high blood glucose levels

– Glucose uptake into tissues increases

• Glucagon– α cells secrete when

blood glucose is low– Glucose is released

from tissues back into blood

Pancreatic axis

• Glucose homeostasis

Figure 26.8

Insulin

Beta cellsof pancreas stimulatedto release insulin intothe blood

Bodycellstake up moreglucose

Blood glucose leveldeclines to a set point;stimulus for insulinrelease diminishes

Liver takesup glucoseand stores it asglycogen

High bloodglucose level

STIMULUS:Rising blood glucoselevel (e.g., after eatinga carbohydrate-richmeal) Homeostasis: Normal blood glucose level

(about 90 mg/100 mL) STIMULUS:Declining bloodglucose level(e.g., afterskipping a meal)

Alphacells ofpancreas stimulatedto release glucagoninto the blood

Glucagon

Liverbreaks downglycogen and releases glucoseto the blood

Blood glucose levelrises to set point;stimulus for glucagonrelease diminishes

Normal

LPL

Triglyceride

LipolysisGlycerol

Free fatty acids

Free fatty acids

Glucose

Synthesis

Insulin

Insulin

Normal Glucose Control• In the post-absorptive period of a normal individual, low basal

levels of circulating insulin are maintained through constant β cell secretion. This suppresses lipolysis, proteolysis and glycogenolysis. After ingesting a meal a burst of insulin secretion occurs in response to elevated glucose and amino acid levels. When glucose levels return to basal levels, insulin secretion returns to its basal level.

• Type I DM: Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. The onset and progression of neuropathy, nephropathy and retinopathy are directly related to episodic hyperglycemia.

• Type II DM: The pancreas retains some β-cell function but effective insulin response is inadequate for the glucose level. Actual insulin levels may be normal or supra-normal but it is ineffective (insulin resistance).

Diabetes mellitus• Type I

– “Childhood” diabetes– Loss of pancreatic β cells– Decreased insulin

• Type II– “Adult” diabetes– Defective signal reception in insulin pathway– Decreased insulin

• Both cause hyperglycemia, glycosuria, lipid breakdown because tissues are deficient in glucose, ketone bodies

Diabetes Mellitus• This is a disease caused by elevated glucose levels• 2 Types of diabetes:

Type I diabetes (10% of cases)– Develops suddenly, usually before age 15.– Caused by inadequate production of insulin because T cell-

mediated autoimmune response destroys beta cells.– Controlled by insulin injections.

Type II diabetes (90% of cases)– Usually occurs after age 40 and in obese individuals, but

genetics, aging, and peripheral insulin resistance also.– Insulin levels are normal or elevated but there is either a

decrease in number of insulin receptors or the cells cannot take it up.

– Controlled by dietary changes and regular exercise.

Triglyceride

LPL

Type 1 Diabetes Mellitus

LipolysisGlycerol

Free fatty acids

Free fatty acids

Glucose

Synthesis

Glucose

Insulin

I

I

I

II

I

I

I

G

G

GG

G

G

GGI

G

G

G

β CellDysfunction

Increased splanchnic

glcoutput

Exxagerated lipolysis

Insulin Resistance

Decreased Glucose Uptake

Type 2 Diabetes: Pathophysiology

Pancreas

Glucose

Insulin

I

I

I

II

I

I

I

G

G

GG

G

G

GGI

G

G

G

InsulinSecretion

Insulin Effects

FOOD

Pancreas

Restrain of HGO Uptake of glucose

Storage In Fat DepotsInhibition of Lipolysis

Insulin and Oral HypoglycemicsThe peptide hormones directly involved in responding to and controlling

blood glucose levels are located in the islets of Langerhans in the pancreas; insulin is secreted by β-cells and glucagon by α2 cells. Diabetes is a disorder of inadequate insulin activity it is associated with episodes of both hyper- and hypo-glycemia. It is the episodes of hyperglycemia that are associated with long-term complications.

Long term complications

• Diabetes is a heterogeneous group of syndromes characterized by the elevation of glucose levels due to a relative or absolute deficiency of insulin; frequently inadequate insulin release is complicated by excess glucagon release.

Table 24-8. Type 1 Versus Type 2 Diabetes Mellitus (DM)

Type 1 DM Type 2 DM

Clinical Onset: <20 years Onset: >30 years

Normal weight Obese

Markedly decreased blood insulin

Increased blood insulin (early);normal to moderate decreased insulin (late)

Anti-islet cell antibodies No anti-islet cell antibodies

Ketoacidosis common Ketoacidosis rare; nonketotic hyperosmolar coma

Genetics 30-70% concordance in twins 50-90% concordance in twins

Linkage to MHC Class II HLA genes

No HLA linkage Linkage to candidate diabetogenic genes (PPARγ, calpain 10)

Pathogenesis Autoimmune destruction of β-cells mediated by T cells and humoral mediators (TNF, IL-1, NO)

Insulin resistance in skeletal muscle, adipose tissue and liver β-cell dysfunction and relative insulin deficiency

Absolute insulin deficiency

Islet cells Insulitis early No insulitis

Marked atrophy and fibrosis Focal atrophy and amyloid deposition

β-cell depletion Mild β-cell depletion

The long term complications of diabetes may be divided into two large groups:

1. Macrovascular: These complications are associated with pathology of the large and medium-sized vessels; this includes CHD, stroke, PVD

2. Microvascular: These complications are due to vascular pathology of the small vessels and include neuropathy, nephropathy, retinopathy

Treatment:• Type I: Type 1s depend on exogenous insulin to prevent

hyperglycemia and avoid ketoacidosis. The goal of type 1 therapy is to mimic both the basal and reactive secretion of insulin in response to glucose levels avoiding both hyper- and hypo-glycemic episodes.

• Type II: The goal of treatment is to maintain glucose concentrations within normal limits to prevent long term complications. Weight reduction, exercise (independent of weight reduction) and dietary modification decrease insulin resistance and are essential steps in a treatment regimen. For many this is inadequate to normalize glucose levels, the addition of hypoglycemic agents is often required, often insulin therapy is required.

Insulin secretion:

Insulin secretion is regulated by glucose levels, certain amino acids, hormones and autonomic mediators.

• Secretion is most commonly elicited by elevated glucose levels; increased glucose levels in β-cells results in increased ATP levels, this results in a block of K+ channels causing membrane depolarization which opens Ca2+ channels.

• The influx of Ca2+ results in a pulsatile secretion of insulin; continued Ca2+ influx results in activation of transcription factors for insulin.

• Oral glucose elicits more insulin secretion than IV glucose; oral administration elicits gut hormones which augment the insulin response.

• Insulin is normally catabolized by insulinase produced by the kidney.

Mechanism of Insulin Release in the Pancreas

INSULIN

• Insulin is a peptide hormone synthesized as a precursor (pro-insulin) which undergoes proteolytic cleavage to form a dipeptide; the cleaved polypeptide remnant is termed protein C.

• Both are secreted from the β-cell, normal individuals secrete both insulin and (but much less) pro-insulin.

• Type 2s are found to secrete high levels of pro-insulin (pro-insulin is inactive) measuring the level of C-protein is a more accurate estimation of normal insulin secretion in type 2s.

Insulin• Human insulin consists of 51 aa in

two chains connected by 2 disulfide bridges (a single gene product cleaved into 2 chains during post-translational modification).

• T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links.

• Bovine insulin differs by 3 aas, pork insulin differs by 1 aa.

• Insulin is stored in a complex with Zn2+ ions.

The synthesis and release of insulin is modulated by:

1. Glucose (most important), AAs, FAs and ketone bodies stimulate release.

2. Glucagon and somatostation inhibit relases

3. α-Adrenergic stimulation inhibits release (most important).

4. β-Adrenergic stimulation promotes release.

5. Elevated intracellular Ca2+ promotes release.

Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane, causing the calcium channel to open up allowing calcium ions to flow inward. The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule.

Mechanism of Insulin Action

• Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity

• Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.

• It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.

• Insulin promotes the uptake of K+ into cells.

The Goal of Insulin TherapyAdministration of insulins are arranged to mimic the normal basal, prandial and post-prandial secretion of insulin. Short acting forms are usually combined with longer acting preparations to achieve this effect.

Rapid Onset and Ultrashort-acting Preparations1. Regular insulin: short acting, soluble, crystalline zinc insulin is usually given

subcutaneously; it rapidly lowers glucose levels. All regular insulin is now made using genetically engineered bacteria; cow and pig no longer used.

2. Lispro, Aspart & Glulisine preparations are classified as ultrashort acting forms with onset more rapid than regular insulin and a shorter duration. These are less often associated with hypoglycemia. Lispro insulin is given 15 minutes prior to a meal and has its peak effect 30-90 minutes after injection (vs. 50-120 minutes for regular insulin).

3. Glulisine can be given anywhere from 15 minutes prior to 20 minutes after beginning a meal.

Intermediate –acting Insulin Preparations

1. Lente insulin: This is a amorphous precipitate of insulin with zinc ion combined with 70% ultralente insulin. Onset is slower but more sustained than regular insulin. It cannot be given IV ( this has not been produced since 2005).

2. Isophane NPH insulin: Neutral protamine Hagedorn insulin is a suspension of crystalline zinc insulin combined with protamine (a polypeptide). The conjugation with protamine delays its onset of action and prolongs it effectiveness. It is usually given in combination with regular insulin.

Prolonged-acting insulin preparations

1.Ultralente: a suspension of zinc insulin forming large particles which dissolve slowly, delaying onset and prolonging duration of action.

2.Insulin glargine: Precipitation at the injection site extends the duration of action of this preparation.

3. Detemir insulin: has a FA complexed with insulin resulting in slow dissolution.

Pump vs. Standard Insulin Therapy

• Insulin Preparations and Treatment• Various types of insulin are characterized by their

onset and duration of action

Insulin Combinations• Various premixed

combinations of various preparations of insulin are available to ease administration. Standard combination use should follow establishment of an acceptable regime of

individual preparations.

Action of Insulin on Various Tissues

Liver Muscle Adipose↓ glucose production ↑ Glucose transport ↑ glucose transport

↑ glycolysis ↑ glycolysis ↑ lipogenesis& lipoprotein lipase activity

↑ TG synthesis ↑ glycogen deposition ↓ intracellular lipolysis

↑ Protein synthesis ↑ protein synthesis

Adverse Effects of Insulin1. Hypoglycemia may occur due to insulin overdose, insufficient

caloric intake (missed meal, improper meal content, delayed meal, etc.). Ethanol consumption promotes hypoglycemic response. Symptoms: ↑ HR, diaphoresis, MS changes, anything (diabetics are usually really good at recognizing hypoglycemic symptoms).

2. Hypokalemia: insulin draws K+ into the cell with glucose (hyperglycemia with normal K+).

3. Anaphylaxis: when sensitized to non-human insulin gets non-human insulin (now rare).

4. Lipodystrophy at injection site5. Weight gain6. Injection complications

Oral Hypoglycemics• These agents are useful in the treatment of type 2s

who do not respond adequately to non-medical interventions (diet, exercise and weight loss).

• Newly diagnosed Type 2s (less than 5 years) often respond well to oral agents, patients with long standing disease (often diagnosed late) often require a combination of agents with or without insulin.

• The progressive decline in β-cell function often necessitates the addition of insulin at some time in Type II diabetes. Oral agents are never indicated for Type Is.

SulfonylureasThese agents promote the release of

insulin from β-cells (secretogogues); tolbutamide, glyburide, glipizide and glimepiride.

• Mechanism: – These agents require functioning β-

cells, they stimulate release by blocking ATP-sensitive K+ channels resulting in depolarization with Ca2+ influx which promotes insulin secretion.

– They also reduce glucagon secretion and increase the binding of insulin to target tissues.

– They may also increase the number of insulin receptors

• Pharmacokinetics: These agents bind to plasma proteins, are metabolized in the liver and excreted by the liver or kidney. Tolbutamide has the shortest duration of action (6-12 hrs) the other agents are effective for ~24 hrs.

SulfonylureasAdverse Effects: These agents tend to cause weight

gain, hyperinsulinemia and hypopglycemia. Hepatic or renal insufficiency causes accumulation of these agents promoting the risk of hypoglycemia. There are a number of drug-drug interactions. Elderly patients appear particularly susceptible to the toxicities of these agents.

• Tolbutamide is asociated with a 2.5X ↑ in cardiovascular mortality.

Onset and Duration• Short acting: Tolbutamide (Orinase)• Intermediate acting: Tolazamide (Tolinase),

Glipizide (Glucotrol), Glyburide (Diabeta)• Long acting: Chloropropamide, Glimerpiride

Meglitinide analogsThese agents (repaglinide (Prandin) and nateglinide (Starlix)) act

as secretogogues.• Mechanism: These agents bind to ATP sensitive K+channels

like sulfonylureas acting in a similar fashion to promote insulin secretion however their onset and duration of action are much shorter. They are particularly effective at mimicking the prandial and post-prandial release of insulin. When used in combination with other oral agents they produce better control than any monotherapy.

• Pharmacokinetics: These agents reach effective plasma levels when taken 10-30 minutes before meals. These agents are metabolized to inactive products by CYP3A4 and excreted in bile.

• Adverse Effects: Less hypoglycemia than sulfonylureas; drugs that inhibit CYP3A4 (ketoconozole, fluconazole, erythromycin, etc.) prolong their duration of effect. Drugs that promote CYP3A4 (barbiturates, carbamazepine and rifampin) decrease their effectiveness. The combination of gemfibrozil and repaglinide has been reported to cause severe hypoglycemia.

Insulin SensitizersTwo classes of oral hypoglycemics work by improving insulin

target cell response; the biguanides and thiazolidinediones.Biguanides:• Metformin is classified as an insulin sensitizer, it increases

glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced.

• Mechanism: Metformin reduces plasma glucose levels by inhibiting hepatic gluconeogenesis. It also slows the intestinal absorption of sugars. It also reduces hyperlipidemia (↓LDL and VLDL cholesterol and ↑ HDL). Lipid lower requires 4-6 weeks of treatment. Metformin also decreases appetite. It is the only oral hypoglycemic shown to reduce cardiovascular mortality. It can be used in combination with other oral agents and insulin.

• Adverse effects: Hypoglycemia occurs only when combined with other agents. Rarely severe lactic acidosis is associated with metformin use particularly in diabetics with CHF. Drug interactions with cimetidine, furosemide, nifedipine and others have been identified.

Insulin Sensitizers

Thiazolidinediones (Glitazones)

• These agents are insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.

• Mechanism of Action: These agents act through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism. Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all improved. HDL levels are also elevated. Accumulation of subcutaneous fat occurs with these agents.

• In the liver: ↓glucose output• In muscle: ↑glucose uptake• In adipose: ↑glucose uptake , ↓FA release• Only pioglitazone may be used in combination with insulin;

the insulin dose must be modified. Rosiglitazone may be used with other hypoglycemic but severe edema occurs when combined with insulin.

• Pharmacokinetics: Both are extensively bound to albumin. Both undergo extensive P450 metabolism; metabolites are excreted in the urine the primary compound is excrete unchanged in the bile.

• Adverse Effects: Fatal hepatotoxicity has occurred with these agents; hepatic function must be monitored. Oral contraceptives levels are decreased with concomitant administration, this has resulted in some pregnancies.

α-Glucosidase InhibitorsThis enzyme hydrolyses

oligosaccharides to monosaccharides which are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucose levels rise modestly and remain slightly elevated for a prolonged period, less of an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia. Sucrase is also inhibited by these drugs.

α-Glucosidase InhibitorsAcarbose and miglitol are two agents of this class used

for type 2 diabetes.Mechanism of action: These agents are oligosaccharide

derivatives taken at the beginning of a meal delay carbohydrate digestion by competitively inhibiting α-glucosidase, a membrane bound enzyme of the intestinal brush border.

Pharmacokinetics: Acarbose is poorly absorbed remaining in the intestinal lumen. Migitol is absorbed and excreted by the kidney. Both agents exert their effect in the intestinal lumen.

Adverse Effects: GUESS (flatulence, diarrhea, cramping). Metformin bioavailability is severely decreased when used concomitantly. These agents should not be used in diabetics with intestinal pathology.

Type 2

• An easy (and over-simplified) way to approach type 2 diabetics is their “glucostat” is set at a higher level. Glucagon remains higher than normal to maintain the higher glucose level, but the insulin response is less pronounced.

Post Prandial Glucose Regulation

Incretin Therapy• Incretins are naturally occurring hormones that the gut

releases throughout the day; the level of active incretins increases significantly when food is ingested.

• Endogenous incretins GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide) facilitate the response of the pancreas and liver to glucose fluctuations through their action on pancreatic β cells and α cells.

• GIP and GLP-1 are the 2 major incretin hormones in humans: 1 – GIP is a 42-aa peptide derived from a larger protein

(ProGIP) and is secreted by endocrine K cells mainly present in the proximal gastrointestinal (GI) tract (duodenum and proximal jejunum).

– GLP-1 is a 30- or 31-aa peptide derived from a larger protein (proglucagon) and is secreted by L cells located predominantly in the distal GI tract (ileum and colon). This protein was first isolated from salivary gland venom of the Gila monster (investigating how these lizards are able to tolerate long periods between meals).

Incretin Therapy Januvia (sitagliptin)

These incretins are released from the gut in response to ingestion of food and collectively contribute to glucose control by:Stimulating glucose-dependent insulin release from pancreatic beta cells (GLP-1 and GIP): Decreasing glucagon production from pancreatic alpha cells (GLP-1) when glucose levels are elevated.

The combination of increased insulin production and decreased glucagon secretion reduces hepatic glucose production when plasma glucose is elevated.

The physiologic activity of incretins is limited by the enzyme dipeptidyl peptidase-4 (DPP-4), which rapidly degrades active incretins after their release.

The Incretin Effect Is Diminished in Type 2 DiabetesLevels of GLP-1 are decreased. The insulinotropic response to GIP is diminished but not absent. Defective GLP-1 release and diminished response to GIP may be important factors in glycemic dysregulation in type 2 diabetes.

Standard vs. Intensive Treatment

Type Glucose Goal HbA1c Goal Treatments BG Monitoring Normal 110mg/dl 6% ------------ -------------- Standard 225-275 mg/dl 8-9% Insulin BID 2-3 per day Intensive 150 mg/dl 7% 3 or more 4-6 per day The trade off between standard and intensive therapy is more frequent hypoglycemic events (hypoglycemic events, seizures and coma) for a marked delay in the onset of diabetic complications both microvascular and macrovascular.HbA1c = Hemoglobin A1c is a useful measure of glucose control over the prior 3-6 months, hyperglycemic episodes result in the nonspecific glycosylation of various proteins.

Symptomatic Hypoglycemia• A note on the treatment of hypoglycemia: Oral glucose/carbohydrate

administration results in a more rapid rise in blood glucose than IV administration; this is due to the involvement of gastrointestinal hormones.