What do the following cells secrete?

(a) Alpha cells

(b) Beta cells

(c) D cells

(d) PP F cells

(a) Glucagon

(b) Insulin 

(c) Somatostatin

(d) pancreatic polypeptide

Stimulates production of glucose in liver 

(gluconeogenesis)

Stimulates breakdown of glycogen  into 

glucose in skeletal muscles and liver cells 

(glycogenolysis)

Stimulates breakdown of triglycerides in 

adipose tissue and fatty acid release 

(lipolysis)

1. Accelerates glucose uptake and utilization by 

cells

2. Stimulates glycogen formation (glycogenesis)

3. Stimulates triglyceride formation in adipose 

tissue (lipogenesis)

4. Stimulates amino acid absorption and 

protein synthesis

Normal blood glucose levels when 

(a) fasting

(b) 2 hours after meals (PP2)

(a) 70-110 mg/dl

(b)<180 mg/dl

Abnormal blood glucose

– Hypoglycemia: 

– Hyperglycemia: 

• Impaired glucose tolerance: 

• Diabetes mellitus: 

- < 70 mg/dl

- >110 mg/dl

-110-180 g/dl

>180mg/dl

Pancreatic disease: e.g., pancreatitis, tumor

– Endocrine disease: e.g., Cushing’s syndrome

– Drug induced: e.g., thiazide diuretics

– Infection: e.g., congenital rubella

Polydipsia

• Polyuria + nocturia

• Glycosuria

• Complications

Complications of DM

• Acute:

– Diabetic ketoacidosis (DKA)

– Hyperosmolar non-ketotic  (HONK) coma 

Complications of DM

Chronic: 

Angiopathy:

• Microangiopathy:

– retinopathy - neuropathy - nephropathy

• Macroangiopathy:

– E.g., coronary artery disease (CAD)

Diet control

• Antidiabetic agents

• Treatment of complications

Insulin

• Oral hypoglycemic agents

Type I diabetes

• Type II diabetes:

– Inadequate control by oral hypoglycemic agents

– Stressful conditions: e.g., infection

– During pregnancy 

• Gestational diabetes

• Bovine

• Porcine

• Human recombinant:

– Least antigenic

– Standardized to 100 U/ml

Injection: SC, IV, IM

– Alternative methods: e.g., pump

• Ultrashort-acting:

• Short-acting:

NPH (Neutral Protamine Hagedorn) insulin

– Lente insulin: reasonably soluble zinc preparation

Insulin Regimens 

• Conventional therapy:

One or two injections per day

– Daily self monitoring of glucose 

– Lower risk of hypoglycemia

Insulin regimens:

Intensive therapy

Multiple daily injections

– Daily self monitoring of glucose and dose adjustment

– Reduction in retinopathy, nephropathy, and 

neuropathy

– Higher risk of hypoglycemia (3-fold more than 

conventional regimen)

Absorption of SC Insulin

• Highly variable:

Among different patients

– Between doses in same patient

Blood flow to site of injection

– Site of injection:

• Abdomen > arm > buttock > thigh

– Depth of injection

– Exercise increases absorption

– Massage of the area increases absorption

Insulin pumps

• Insulin pens (insulin containing cartridges)

• Inhaled insulin

• Transdermal patches

• Oral formulas (designed to resist insulin 

digestion in the GIT)

Indwelling catheter delivers basal insulin

•

Patient can program device to modify delivery rate

Exubera:

(a) Preparation

(b) powder

(c) delivery

(a) Short - acting insulin preparation

(b) fine dry powder

(c) Non-invasive insulin delivery

What enters the blood faster? Inhaled insulin or SC injection?

Where must the drug reach?

Inhaled insulin

Alveoli in the lung

Complications of Insulin Therapy

• Systemic:

Hypoglycemia → most dangerous

–

Insulin allergy → rare with human insulin

–

Insulin resistance

Complications of Insulin Therapy

Local

Lipoatrophy

–

Hypertrophy

Oral Hypoglycemic Agents

(5)

Sulfonylureas

•

Biguanides

•

Meglitinides

•

Thiazolidinediones (TZDs, glitazones)

•

Alpha-glucosidase inhibitors

Inhibit K channels on β-cell → causing depolarization → ↑ calcium entry → ↑ insulin release

What do sulfonylureas require?

Which diabetes are they useful for?

Functional B cells to work

Only useful for type 2 not type 1

What do sulfonylureas bind to?

(b) metabolised

(c) excreted

(a) Plasma proteins

(b) Liver

(c) Kidney

(a) Elderly

(b) Renal disease

(c) Liver disease

NSAIDs, coumarins, alcohol, MAO inhibitors, some antibacterials (sulfonamides, chloramphenicol)

–

Cimetidine (inhibits metabolism)

Hypoglycemia (esp. chlorpropamide)

Gi disturbances

Jaundice

Allergic skin reactions

Decrease gluconeogenesis in liver

Increase glucose uptake in skeletal muscles

First choice drug in patients with Type 2 DB

Can be combined with sulfonylureas and insulin

Anorexia: Dose dependent can be severe

Nausea, diarrhea, metallic taste

Lactic acidosis (acidification of blood)

What is the only approved form of biguanides?

What are its 2 forms?

Metformin (dimethylbiguanides)

• 2 tablet forms:

1. Glucophage™

• Glucophage XR™ (extended-release tablets)

What are meglinitides?

What are they similar to?

Duration of action?

Short acting insulin secretagogues.

Similar in action to sulfonylureas.

Half life is 1 hour.

Type 2 DM.

Can be combined with metformin.

Examples of meglitinides:

repaglinide

nateglinide

• Activate a transcription regulator, PPARγ (peroxisome proliferator-activated receptor gamma) →

1. modulate lipogenesis in adipocytes

• improve glucose uptake in skeletal muscles

• reverse insulin resistance

Indications of TZDs:

Type 2 DM

–

Alone or combined with metformin, sulfonylurea

Congestive heart failure

Myocardial ischemia

May cause liver injury (monitor liver f unction)

Rosiglitazone???

What do you use for (a) Impaired insulin secretion

(b) Glucose uptake and utilisation

(a) Sulfonylureas and meglitinides

(b) Metformin and TZDs