Diabetes Mellitus

Prof Fawaz Ammari F.R.C.P (London)

JUST (University)

Diabetes Mellitus

Definition Classification Etiology Diagnosis Treatment Complication

Proinsulin
Ca2+-dependent endopeptidases PC2 (PC3)

C peptide
MW 5808

Insulin
A Chain

B Chain
PC3

Insulin release: normal levels

Units: 1 U = 36 g, i.e. 28 U/mg Daily secretion in humans: 40 - 50 U Basal plasma insulin: 12 U/ml Postprandial insulin: up to 90 U/ml
Glucose, mg/dl
120

Meal

100

Insulin, U/ml

80 80

60
40

Basal
Minutes 0 30 60 90 120

20

Insulin metabolism

Secreted into portal circulation

50% of degradation in liver 50% of degradation in other target tissues and kidney Enzymatic degradation follows receptormediated endocytosis

Plasma half-life: 3 - 5 min.

Circulates as free monomer

Effects of insulin:
Liver

Stimulates
glycogen synthesis triglyceride synthesis

Inhibits
glycogenolysis ketogenesis gluconeogenesis

Skeletal

Muscle
protein degradation glycogenolysis

glucose uptake protein synthesis glycogen synthesis

Adipose

tissue
lipolysis

glucose uptake triglyceride storage

Promotes anabolic processes

Inhibits catabolic processes

Abnormalities due to insulin deficiency

Hyperglycemia

Underutilization of glucose Overproduction of glucose

Increased lipolysis Acidosis - Increased conversion of fatty acids to ketoacids (acetoacetic and b-hydroxybutyric) Increased plasma triglycerides and LDL; decreased HDL Osmotic diuresis, plasma hyperosmolarity, dehydration, hypovolemia, polydipsia Depletion of intracellular and whole-body K+

Definition of DM

D M is a group of metabolic diseases characterized by hyerglycemia resulting from defects in insulin secretion .insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction,and failure of various organ,especially the eye,kidneys,heart,and blood vessels.

The worldwide pandemic of type 2 diabetes

350
World wide diabetes prevalence (millions)

300 300 250 200 150 150 100

2000 2010 2025

221

International Diabetes Federation Diabetes Atlas 2000; Amos et al. Diabet Med 1997;14 (Suppl 5):S1-S85.

Prevalence of type 2 diabetes in selected populations aged 30-64 years (Age standardised)

China

Bantu
Polynesian

Polynesian Cook Islands

White US

Black US
Hispanic US Chinese Mauritius Asian Indian Fiji Pima Indian

10

20

30

40

50

Prevalence (%)

Top ten countries for estimated number of adults with diabetes, 1995 and 2025
Country 1995 (millions) Country 2025 (millions)

Rank 1 India 2 China 3 U.S. 4 Russian Fed. 5 Japan 6 Brazil 7 Indonesia 8 Pakistan 9 Mexico 10 Ukraine All other countries Total

19.4 16.0 13.9 8.9 6.3 4.9 4.5 4.3 3.8 3.6 49.7 135.3

India China U.S. Pakistan Indonesia Russian Fed. Mexico Brazil Egypt Japan

57.2 37.6 21.9 14.5 12.4 12.2 11.7 11.6 8.8 8.5 103.6 300.0

Diabetes Mellitus in the US: Health Impact of the Disease

6th leading cause of death

Renal failure*

Life expectancy 5 to 10 yr

Blindness*

Diabetes

Cardiovascular disease 2X to 4X Nerve damage in 60% to 70% of patients

Amputation*

*Diabetes is the no. 1 cause of renal failure, new cases of blindness, and nontraumatic amputations Diabetes Statistics. October 1995 (updated 1997). NIDDK publication NIH 96-3926. Harris MI. In: Diabetes in America. 2nd ed. 1995:1-13.

Diabetes Mellitus in the US: Higher Mortality Risk

Relative Risk*
Age Group (yr) 45-64 65-74 Men 3.4 2.0 Women 4.6 3.1

75

1.6

2.0

*For persons with type 1 or 2 diabetes vs nondiabetic individuals Geiss LS et al. In: Diabetes in America. 2nd ed. 1995:233-257.

Annual Healthcare Costs for Diabetes Patients, 1992 ($ Billions)

Emergency room $1.3 (1%)

Dental $1.4 (1%)

Home healthcare $4.0 (4%) Drugs and DME $9.9 (9%)

Inpatient hospital $65.2 (63%)

$105 Billion

Outpatient hospital $12.5 (12%) DME = durable medical equipment

Professional office visits $11.0 (10%)

Rubin RJ et al. J Clin Endocrinol Metab. 1994;78:809A-809F.

Classification of Diabetes Mellitus

Type 1 diabetes* (b-cell destruction, usually leading to absolute insulin deficiency) immune mediated idiopathic Type 2 diabetes* (may range from predominantly insulin resistance with relative insulin deficiency to a predominantly secretory defect with insulin resistance) adult onset obesity Impaired glucose tolerance Gestational diabetes

ADA. Diabetes Care. 1997;20:1183-1197. *Patients with any form of diabetes may require insulin treatment at some stage of their disease; such use of insulin does not, of itself, classify the patient

Etiologic Classification of Diabetes Mellitus

Genetic defects of b-cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug- or chemical-induced Physiologic stress (eg, infection) Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes
ADA. Diabetes Care. 1997;20:1183-1197.

Criteria for the Diagnosis of Diabetes: 1997 ADA Guidelines

Plasma Glucose Level (mg/dL) Stage of Glycemic Control
Normal IFG or IGT Diabetes*

Fasting Plasma Glucose

<100 100 125

OGTT (2-hr Postload Glucose)

<140

140 199
126 200

*Third criterion: 200 mg/dL casual plasma glucose (regardless of time since last meal) plus symptoms of diabetes (polyuria, polydipsia, unexplained weight loss) ADA. Diabetes Care.1997;20:1183-1197.

Glucose Tolerance Categories

FPG
Plasma glucose (mg/dL)

2-h PPG (OGTT)

240
220

Diabetes Mellitus
Diabetes Mellitus

Plasma glucose (mmol/L)

200
180 160

11.1

IGT

140 126 100

120

7.0

IFG
Normal 5.5 Normal

80 60

American Diabetes Association. Diabetes Care. 2007;30(suppl 1)

Pathogenesis of Type I DM
Genetic HLA-DR3/DR4 Environment ? Viral infe..??

Autoimmune Insulitis cell Destruction Severe Insulin deficiency

Type I DM

Pathogenesis of Type II DM
cell defect Genetic Abnormal Secretion Environment Obesity ??? Insulin resistance

Relative Insulin Def.

cell exhaustion

Type II DM

IDDM

Natural History of Type 2 Diabetes Impaired Undiagnosed

glucose tolerance diabetes Known diabetes

Insulin resistance

Insulin secretion Postprandial glucose Fasting glucose

Microvascular complications Macrovascular complications

Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789

Type-I

Type-II

Age: < 40 Years Duration: Weeks Ketonuria: Common Insulin- Dependent Autoantibody: Yes Family History: No Insulin levels: very low Islets: Insulitis Complications:
Acute & Metabolic

> 40 Years Months to years Rare Independent * No Yes Normal or high * Normal / Exhaustion Complications
Late and vascular.

Clinical Feature

Polyuria and thirst Weakness or fatigue Polyphagia and weight loss Blurring of vision Vulvovaginitis or pruritus Nocturnal enuresis Asymptomatic May presented with acute complication May presented with late complications

Management of Diabetes
DIET
EXERCISE OHA INSULIN

First international consensus EASD/ADA June 06

A new sense of urgency to treat more effectively and quickly
STEP 1 Initial therapy STEP 2 After 23 months select 1 additional agent Basal insulin STEP 3 Adjust therapy

Call to action : 3 steps to keep control

Lifestyle intervention (HbA1c 12%) Metformin (HbA1c 1.5%)

HbA1c 7%

(HbA1c 1.52.5%)
Sulfonylureas

(HbA1c 1.5%) Thiazolidinedione (HbA1c 0.51.4%)

HbA1c 7%

Start or intensify insulin therapy Add a third oral agent if cost-effective

Type 2 diabetes is a progressive disease with steadily worsening glycemia Addition of medication is the rule not the exception to maintain treatment goals

Adapted from Nathan DM, et al. Diabetologia 2006;49:171121

DIET

Diet is the coroner stone of manag of DM There is no stander diabetic diet Diet must be individualized Flexibility in use ordinary food is important Diet must be of adequate calories for maintaining weight for adult,normal growth for children,increased metabolic needs in pr Diet must contain 10-20% of protein 20-30% fat and 50-60% carbohydrate Fiber intake must be increase

Control of blood glucose is essential in diabetic patients with any possible method (Diet, Oral agents, or Insulin) Otherwise, The complications of diabetes will appear

Pathophysiology of Type 2 DM

Insulin resistance
insulin receptor number insulin receptor kinase activity Post-receptor defects

GLUT4 translocation from impaired signaling

Impaired islet function

Loss of first phase insulin secretion secretion of proinsulin Defective pulsatile insulin secretion Deposition of islet amyloid polypeptide

Treatment of Type 2 Diabetes

Diet

and exercise

80 % of Type 2 diabetics are obese

caloric intake insulin sensitivity physical exercise first line of treatment recent clinical trial showed that exercising at least 30 minutes a day reduces Type 2 risk more effectively than medication

Treatment of Type 2 Diabetes

Monotherapy

with oral agent

Combination
Insulin

therapy with oral agents

+/- oral agent

insulin required in 20-30% of patients

With duration of the disease, more intensive therapy is required to maintain glycemic goals

Oral Drug Therapy for Type 2 DM

Sulfonylureas Repaglinide Nateglinide Biguanides

Thiazolidinediones
Acarbose Miglitol

} } }

Insulin secretagogues

Insulin sensitizers Inhibitors of CHO absorption

Sulfonylureas: Metabolism & Excretion

Metabolized in the liver Hepatic dysfunction will alter pharmacokinetics Excretion Second generation: significant fecal excretion Glyburide -50% Glimeperide - 40%

Clinical Uses of Sulfonylureas

Hypoglycemic

agents for treatment of Type 2 diabetes mellitus Act by increasing endogenous insulin secretion \ not indicated for Type 1 Most effective when cell function has not been severely compromised Increased insulin secretion favors lipogenesis
Most

appropriate in non- or mildly obese Up to 160 % of ideal body weight

Adverse Effects of Sulfonylureas

Severe hypoglycemia
Overdose Early in treatment Most common with glyburide

Weight gain Erythema, skin reactions Blood dyscrasias (abnormal cellular elements) Hepatic dysfunction and other GI disturbances

Contraindications for Sulfonylureas

Pregnancy

Surgery
Severe infections

Severe stress or trauma

Severe hepatic or renal failure

Insulin therapy should be used in all of these

METFORMIN (Profile)
Class: biguanide Mode of action: - Decreases hepatic glucose production
- Enhances muscle glucose uptake

* As monotherapy or combination with other drugs * Useful in obese pationts with dyslipedemia Contraindications: renal failure - Cr>1.5 mg/dl - liver failure
Congestive heart failure - DKA - Sepsis Dye procedures (temporarily discontinue) alcoholism

Adverse Effects:

Lactic acidosis (very rare) - Anorexia nau sea - diarrhea (transient) No weight gain - No hypoglycemia - No hyperinsulinemia

REPAGLINIDE (Profile)
Class: Meglitinides Mode of Action: Stimulating release of insulin via
distinct beta cell bindings sites a part from sulfonylurea binding site * Benzoic acid derivatives * has greater effect postprandially * Fast onset and offset action Contraindication: DKA - Type 1 diabetes hypersensitivity Adverse effects: hypoglycemia - hypersensitivity weight gain

ACARBOSE
Class: alpha -Glucosidase inhibitor

(Profile)

Mode of Action: - inhibiting alpha-glucosidase locally in small intestine- Slows intestinal absorption of carbohydrates- reduces postprandial hyperglycemia * As monotherapy or combination with sulfonylurea * Most useful in patients with exaggerated postprandial hyperglycemia Contraindications: IBD, Ulcer, malabsorption, partial
intestinal obstraction

Adverse Effects: Flatulence - bloating (very common but may

subside over the time) * monitoring of transaminase / 3 months

ROSIGLITAZONE
Class: thiazolindendione

Mode of Action: binds to peroxisome profilerator activated receptor -gamma regulation of glucose and fatty acid metabolism (young et al 1998) * Significantly improved FBS & HbA1C in type 2 diabetics ( clinical investigator news 1998)
Adverse effects: Rosiglitazone = placebo

However; minor anemia - fluid retention weight gain

New Diabetes Agents

Pramlintide

Synthetic Amylin Taken as pre-meal subcutaneous injections

Insulin is continued

Type 2 and Type 1 patients

Exenatide

Incretin mimetic

Possesses the effects of GLP-1 Resistant to breakdown by DPP-4

Twice daily subcutaneous injections with pen device Type 2 DM patients not controlled on sulfonylurea, metformin or TZD

Sitagliptin, Vildagliptin

DPP-4 inhibitors Once daily oral agent Type 2 DM patients as monotherapy or combination with metformin, glimepiride or TZD

Insulin

Insulin is a protein hormone consisting of two longchain peptides (the A-chain containing 21 amino acids and the B-chain containing 30) which are connected by two pairs of sulphur atoms (termed disulphide bridges). Porcine insulin differs from human insulin in only a single amino acid

Bovine insulin has only two additional substitutions.

Insulin structure

The structure (amino-acid sequence) of human insulin. Each small circle refers to an amino acid. The highlighted residues are those that differ in porcine and bovine insulins, as show.

Insulin type Rapid acting (R)

Onset 0.5-1h

Duration 6-8h

Peak 2-3h

Other Characteristics SQ injection does not produce sharp physiologic peak; give 30 min before meal Give 10-15 min before meals

Very rapid acting (lispro, aspart, glulisine)

0.250.5h

4-6h

1-2h

Intermediate (N)

2-4h

10-14h

4-8h

Do not pre-mix with very rapid acting insulins

Long acting (glargine, detemir)

gradual

~24h

None or Must not be diluted or mixed small with any other insulin or solution

Insulin Preparations
Ultra fast/ultra short-acting lispro regular
Plasma [Insulin]
from LillyDiabetes.com

Short-acting
Intermediateacting

NPH lente ultralente

from lantus.com

Long-acting
Ultra long-acting
0 4

glargine
8 12 16 20 24

Insulin treatment regimens

Conventional insulin treatment

1 or 2 daily subcutaneous injections

mixture of short- and intermediate or long-acting

insulins

total

regular lente

am

12

pm

12

am

12

Insulin treatment regimens

Intensive insulin treatment

Frequent monitoring of blood glucose 3 or more daily injections of insulin Some regular alone, some combined regular and

intermediate- or long-acting Adjusted to needs of individual patient regular lente

4

am

12

pm

12

am

12

lispro glargine
4

am

12

pm

12

am

12

am

12

pm

12

am

12

Insulin treatment regimens

Continuous subcutaneous insulin infusion

Insulin pump with lispro or regular insulin Programmed basal delivery

allows control of dawn phenomenon

Patient-triggered bolus before meals

Continuous infusion
regular or lispro
4

am

12

pm

12

am

12

Incidence of DKA is increased vs. that with multiple daily injections

Guideline on dosage of insulin

The correct dose of insulin is that which achieve the best glycemic control The daily insulin dose is 0.5-0.6 iu/kg /daily The start dose for normal wt patient 15-20iu The start dose for obese patient 25-30 iu 2/3 of the dose in the morning 1/3 in the eve 1/3 rapid acting 2/3 intermediate acting

Age Weight Stage of puberty Duration of diabetes Nutritional intake Exercise patterns Results of BG monit Intercurrent illness

Insulin dosage depends on many factors

Adverse Effects of Insulin Therapy

Hypoglycemia
Especially dangerous in Type 1 diabetics Glucose or glucagon treatment

Allergy and resistance to insulin

Local cutaneous reactions or systemic Switch to less antigenic form or desensitization

Lipohytertrophy
Due to lipogenic effect of insulin when small area used for frequent

injections Absorption from such sites is unpredictable

Lipoatrophy
Due to impurities: switch to highly purified insulin Lipogenic effect of insulin can repair lesion

Insulin edema- transient, rare