Diabetes Mellitus

 Diabetes mellitus (DM) is a group of diseases characterized by high levels of blood glucose
resulting from defects in insulin production, insulin action, or both.

 The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by
chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting
from defects in insulin secretion, insulin action, or both.

 The effects of diabetes mellitus include long–term damage, dysfunction and failure of various
organs.

 Diabetes mellitus may present with characteristic symptoms such as Polydipsia (excessive
sweating), polyuria (urinate often), Polyphagia (excessive eating), blurring of vision, and weight
loss.

 In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and
lead to stupor, coma and, in absence of effective treatment, death.

 Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient
to cause pathological and functional changes may be present for a long time before the
diagnosis is made.

Types of Diabetes

 Type 1 Diabetes Mellitus

 Type 2 Diabetes Mellitus

 Gestational Diabetes

Type 1 diabetes

 Was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes.

 Type 1 diabetes develops when the body’s immune system destroys pancreatic beta cells, the
only cells in the body that make the hormone insulin that regulates blood glucose.

 This form of diabetes usually strikes children and young adults, although disease onset can occur
at any age.

 Type 1 diabetes may account for 5% to 10% of all diagnosed cases of diabetes.

 Risk factors for type 1 diabetes may include autoimmune, genetic, and environmental factors.
Type 2 diabetes

 Was previously called non-insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes.

 Type 2 diabetes may account for about 90% to 95% of all diagnosed cases of diabetes.

 It usually begins as insulin resistance, a disorder in which the cells do not use insulin properly. As
the need for insulin rises, the pancreas gradually loses its ability to produce insulin.

 Type 2 diabetes is associated with older age, obesity, family history of diabetes, history of
gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity.

 African Americans, Hispanic/Latino Americans, American Indians, and some Asian Americans
and Native Hawaiians or Other Pacific Islanders are at particularly high risk for type 2 diabetes.

Gestational diabetes

 A form of glucose intolerance that is diagnosed in some women during pregnancy.

 Gestational diabetes occurs more frequently among African Americans, Hispanic/Latino

Americans, and American Indians. It is also more common among obese women and women
with a family history of diabetes.

 During pregnancy, gestational diabetes requires treatment to normalize maternal blood glucose
levels to avoid complications in the infant.

 After pregnancy, 5% to 10% of women with gestational diabetes are found to have type 2
diabetes.

 Women who have had gestational diabetes have a 20% to 50% chance of developing diabetes in
the next 5-10 years.

INSULIN

• Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialized
target cells

• Influences cell growth and the metabolic functions of a wide variety of tissues.

Available Insulin Preparations

1. Rapid-acting insulin

2. Short-acting insulin

3. Intermediate-acting and long-acting insulins

Rapid-acting insulin

 Three injected rapid-acting insulin analogs — insulin lispro, insulin aspart, and insulin glulisine —
are commercially available.

 The rapid-acting insulins permit more physiologic prandial insulin replacement because their
rapid onset and early peak than regular insulin.
  They have the additional benefit of allowing insulin to be taken immediately before the meal
without sacrificing glucose control.

Short-acting insulin

Regular insulin is a short-acting soluble crystalline zinc insulin that is now made by recombinant
DNA techniques to produce a molecule identical to that of human insulin.

Its effect appears within 30 minutes, peaks between 2 and 3 hours after subcutaneous injection,
and generally lasts 5–8 hours.

Intermediate-acting and long-acting insulins

a. NPH (neutral protamine Hagedorn, or isophane) insulin— - NPH insulin is an intermediate-

acting insulin whose absorption and onset of action are delayed by combining appropriate
amounts of insulin and protamine

b. Insulin glargine— Insulin glargine is a soluble, “peak less” long-acting insulin analog. This
product was designed to provide reproducible, convenient, background insulin replacement.

c. Insulin detemir— This insulin is the most recently developed long-acting insulin analog. Insulin
detemir has a dose-dependent onset of action of 1–2 hours and duration of action of more than
12 hours. It is given twice daily to obtain a smooth background insulin level.

Complications of Insulin Therapy

Hypoglycemia
Insulin allergy
Immune insulin resistance
Lipodystrophy at Injection Sites
Increased Cancer Risk

Oral Anti-Diabetic Agents

There are currently eight classes of oral anti-diabetic agents:

i. Biguanides
ii. Insulin Secretagogues – Sulfonylureas
iii. Insulin Secretagogues – Non-sulfonylureas
iv. α-glucosidase inhibitors
v. Thiazolidinediones (TZDs)
vi. Dipeptyl peptidase-iv inhibitors
vii. Glucagon-like peptides (GLP – 1) Agonists
viii. Selective Sodium-glucose transporter-2 (SGLT2) inhibitor
Biguanides (Metformin)

Mechanism of action

 Primary effect is to reduce hepatic glucose production through activation of the enzyme AMP-
activated protein kinase (AMPK).

 Has a half-life of 1.5–3 hours

 Biguanides are recommended as first-line therapy for type 2 diabetes

 Because metformin is an insulin-sparing agent and does not increase body weight or
provoke hypoglycemia

The most common toxic effects of metformin are gastrointestinal:

 Anorexia
 Nausea
 Vomiting
 Abdominal discomfort
 Diarrhea

Black Box Warning

 May Cause Lactic Acidosis

Insulin Secretagogues Sulfonylureas

Mechanism of Action

Insulin Release from Pancreatic Beta Cells

Initial effect is to increase beta cell insulin secretion;

Depolarization opens a voltage-gated calcium channel and results in calcium influx and the
release of preformed insulin.

Reduction of Serum Glucagon Concentrations

Indirect inhibition due to enhanced release of both insulin and somatostatin, which inhibit
alpha-cell secretion.

Half – Life: 5-9 Hrs

Contraindicated in:

 Type 1 DM
 Severe Renal Impairment

Monitoring:

 Half-life is prolonged in renal failure

  Efficacy may decrease in prolonged use
First Generation

 Tolbutamide
 Chlorpropamide

Second Generation

 Glyburide
 Glipizide
 Glimepiride

INSULIN SECRETAGOGUE: MEGLITINIDE

Repaglinide is the first member of the meglitinide group of insulin secretagogues.

Increase Insulin secretion by blocking ATP potassium channels on beta islet cells, which
facilitates calcium entry through calcium channels;

 (Increased intracellular calcium stimulates insulin release)

There is no sulfur in its structure, so repaglinide may be used in type 2 diabetics with sulfur or
sulfonylurea allergy.

Half Life: 1hr

Contraindications:

 Type 1 DM

 The use with sulfonylureas may increase cardiovascular events

INSULIN SECRETAGOGUE: D-PHENYLALANINE DERIVATIVE

Nateglinide

Increase insulin secretion via binding K+ channels on beta islet cells.

Amount of insulin released is dependent upon existing glucose levels.

The incidence of hypoglycemia with nateglinide may be the lowest of all the secretagogues, and
nateglinide has the advantage of being safe in those with very reduced renal function.

Half Life: 1.2 – 3Hr

Contraindications

Not to be used in combination with insulin secretagogue

THIAZOLIDINEDIONES

Acts to decrease insulin resistance.

Tzds are ligands of peroxisome proliferator-activated receptor (PPAR)

In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose
uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins
involved in energy regulation.

Tzds also regulate adipocyte apoptosis and differentiation.

Improves target-cell response to insulin; decreases hepatic gluconeogenesis; depends on the presence
of insulin activity

These class of medications has been linked to:

 Weight Gain
 Increased risk of heart failure
 Fractures
These medications generally aren’t a first-choice treatment.

Pioglitazone

Is metabolized by CYP2C8 and CYP3A4 to active metabolites.

May be taken once daily; the usual starting dose is 15–30 mg/d, and the maximum is 45 mg/d.

Half Life: 3-7 hrs

Approved as a monotherapy and in combination with metformin, sulfonylureas, and insulin for the
treatment of type 2 diabetes.

The risk of bladder cancer appears to be cumulatively increased with high doses.

Rosiglitazone

Rapidly absorbed and highly protein-bound.

It is metabolized in the liver to minimally active metabolites, predominantly by CYP2C8 and to a lesser
extent by CYP2C9.

It is administered once or twice daily; 2–8 mg is the usual total dose.

Half life: 3-4 hrs

Rosiglitazone shares the common Tzd adverse effects but appears to carry more cardiovascular risk than
pioglitazone.
ALPHA-GLUCOSIDASE INHIBITORS

Acarbose and miglitol

are competitive inhibitors of the intestinal α-glucosidases and reduce post meal glucose
excursions by delaying the digestion and absorption of starch and disaccharides.

Inhibits metabolism of sucrose to glucose and fructose

Both acarbose and miglitol are taken in doses of 25–100 mg just before ingesting the first
portion of each meal;

Prominent adverse effects include:

 Flatulence
 Diarrhea
 abdominal pain
 result from the appearance of undigested carbohydrate in the colon that is then fermented into
short-chain fatty acids, releasing gas.

Hypoglycemia should be treated with glucose (dextrose) and not sucrose, whose breakdown
may be blocked.

These drugs are contraindicated in patients with inflammatory bowel disease or any intestinal
condition that could be worsened by gas and distention.

Acarbose has been associated with reversible hepatic enzyme elevation and should be used with
caution in the presence of hepatic disease.

Dipeptyl peptidase-iv inhibitors

Increases and prolongs incretin hormone activity, which is inactivated by DPP-4 enzymes

Incretins increase insulin release and synthesis from pancreatic beta cells and reduce glucagon
secretion from pancreatic alpha cells

Half – Life: 12.4 hr

Medications:

 Sitagliptin
 Saxagliptin
 Linagliptin

Contraindication

 May increase the risk factor for heart failure

  Monitor for sign and symptoms
 May Worsen renal failure

Selective Sodium-glucose transporter-2 (SGLT2) inhibitor

Lowers the renal glucose threshold.

Lowering the renal glucose threshold results in increased urinary glucose excretion

Half Life: 10.6 hr (100mg) 13.1hr (300mg)

Indicated as an adjunct to diet and exercise to improve glycemic control with type 2 DM

Medications:

 Dapagliflozin
 Empagliflozin

Contraindication

 May increase the risk of amputation

 Not for patient with End Stage Renal Disease
 May cause hyperkalemia
 Genital mycotic infection may occur
 Increased risk of UTI

Glucagon-like peptides (GLP – 1) Agonists

Affect glucose control through several mechanism:

 Enhancement of glucose dependent insulin secretion

 Slowed gastric emptying and post prandial glucagon and of food intake

Half – Life: 2.4 hr

Can be used as an add-on to metformin

Medications:

 Exanatide
 Liraglutide

Contraindications

 Acid or Sour Stomach

 Belching
 Heartburn
 Indigestion
 Nausea
 Vomiting

Not meant for patient with severe gastrointestinal disease