3. Diabetes Mellitus
• Diabetes mellitus is a group of metabolic diseases
characterized by hyperglycemia resulting from defects
in insulin secretion, insulin action, or both
• Hyperglycemia, glycosuria, hyperlipidemia,
hyperuricemia
• Fasting plasma glucose >7.0 mmol/l (126mg/dL)
• Two-hour plasma glucose ≥ 11.1 mM (200 mg/dL)
• HbA1c ≥ 6.5%
• Multi-organ dysfunction syndrome
3Dr. Aditi M. Panditrao
4. Global Burden
• Nov 2014 – 347 million worldwide
• India – 65.1 million
• 7th leading cause of death in the world by the year 2030
• 90% - Type 2 DM
• 2012 – 1.5 million deaths
4Dr. Aditi M. Panditrao
6. Types
• Type 1 –
• Immune β-cell destruction or idiopathic, leading to absolute
insulin deficiency
• Type 2 –
• Insulin resistance with relative insulin deficiency or insulin
secretory defect with insulin resistance
• Gestational Diabetes –
• Diabetes diagnosed in the second or third trimester of pregnancy
that is not clearly overt diabetes
• Specific types of diabetes due to other causes –
• Neonatal diabetes, maturity-onset diabetes of the young [MODY],
diseases of the exocrine pancreas (such as cystic fibrosis), and
drug- or chemical-induced diabetes (such as in the treatment of
HIV/AIDS or after organ transplantation
6Dr. Aditi M. Panditrao
11. Pathogenesis of DM type 2
• Beta cell dysfunction
• Decreased Sensitivity to stimuli
• Decreased number
• Insulin Resistance
• Free Fatty Acids
11Dr. Aditi M. Panditrao
12. Clinical Features
• Polyuria, polydipsia, polyphagia
• Delayed wound healing, sepsis
• Acute complications – Ketoacidosis
• Long term complications – Retinopathy,
neuropathy, nephropathy, cardiovascular
events
12Dr. Aditi M. Panditrao
13. Goals of treatment
• Achieve near normal glycaemia
• Alleviate the symptoms related to hyperglycemia
• Prevent or reduce the acute and chronic
complications of diabetes
• Good quality of life, near normal life expectancy
13Dr. Aditi M. Panditrao
25. First-Generation Sulfonylureas
• Tolbutamide
• Its half-life is relatively short (6 hr.)
• Is the safest sulfonylurea for use in elderly
• Chlorpropamide
• Has a long half-life (32 hr.)
• Contraindicated in elderly patients
• Tolazamide
• Comparable to chlorpropamide in potency but shorter
acting (half life 7 hr.)
25Dr. Aditi M. Panditrao
26. Second-Generation Sulfonylureas
• Glyburide
• Has few adverse effects other than hypoglycemia.
• Contraindicated in the presence of hepatic and renal
insufficiency
• Glipizide
• Has the shortest half-life (3 hr.)
• Taken 30 mins before meals
• Glimepiride
• Has the lowest dose of any sulfonylurea (a single daily
dose of 1 mg)
26Dr. Aditi M. Panditrao
27. Meglitinide
• Repaglinide
• MOA – same as Sulfonylureas
• Very fast onset of action, with a peak effect within
1 hour, the duration of action is 5–8 hr.
• Metabolism – Liver, Kidney
• Secondary Failure
• Is indicated for use in controlling postprandial
glucose excursions
• Hypoglycemia is less
27Dr. Aditi M. Panditrao
28. D-phenylalanine derivatives
• Nateglinide
• May have a special role in the treatment of isolated
postprandial hyperglycemia
• Dose titration is NOT required
• Is ingested just prior to meals, absorbed within 20 min.
And peak concentration of <1 hour
• Incidence of hypoglycemia - lowest
• It is safe in individuals with very reduced renal function
28Dr. Aditi M. Panditrao
29. Biguanides: Metformin
• Decrease hepatic glucose production through
activation of the enzyme AMP-activated protein
kinase (AMPK)
• Euglycemic conditions (no effect in non diabetics)
• Does not stimulate pancreatic β cells
• Inhibit Renal gluconeogenesis, slowing of glucose
absorption from the gastrointestinal tract, with
increased glucose to lactate conversion by enterocytes,
direct stimulation of glycolysis in tissues, increased
glucose removal from blood, and reduction of plasma
glucagon levels
29Dr. Aditi M. Panditrao
30. Metformin (contd.)
• Insulin necessary for action
• Metformin has a half-life of 1.5–3 hours, is not
bound to plasma proteins, is not metabolized, and is
excreted by the kidneys as the active compound
• Insulin resistance syndrome
• Insulin sparing – Weight loss
• Side effects – anorexia, nausea-vomiting, abdominal
discomfort, diarrhea,
• Contraindicated in alcoholism and anoxic states
(cardiopulmonary dysfunction) because of an
increased risk of lactic acidosis
30Dr. Aditi M. Panditrao
33. Thiazolidinediones (Tzds)
• Tzds are ligands of peroxisome proliferator-activated
receptor gamma (PPAR-γ)
• PPAR is part of the steroid and thyroid superfamily of
nuclear receptors involved in lipid and glucose
metabolism, and insulin signal transduction.
• Pioglitazone – Bladder Cancer – Ban and reinstatement
• Rosiglitazone – Banned (2010) - MI, CHF, stroke and
death
33Dr. Aditi M. Panditrao
34. Thiazolidinediones (Tzds)
• Reverse insulin resistance – Euglycemics
• Adipocyte differentiation, uptake of fat and glucose,
hepatic gluconeogenesis decreased
• Absorbed within 2 hours of ingestion
• Metabolism – Liver (can be used in renal impairment)
• Side effects – Weight gain, edema, headache, myalgia
and mild anaemia. Fractures in older females
34Dr. Aditi M. Panditrao
37. Alpha Glucosidase Inhibitors
• Acarbose & Miglitol
• Inhibits α-glucosidase - Reduce digestion and
absorption of polysaccharides and disaccharides.
• Promotes release of GLP-1
• Antihyperglycaemic
• Taken before meals. Absorption – low
• Side effects: flatulence, diarrhea, and abdominal pain
(undigested carbohydrate is fermented in colon and
releases gas), mild to moderate elevations of hepatic
transaminases
37Dr. Aditi M. Panditrao
39. Bile Acid Sequestrants
• Colesevelam is used for type 2 DM.
• The mechanism of action involves:
– An interruption of the enterohepatic circulation
(decrease in hepatic glucose output)
– A decrease in farnesoid X receptor (FXR) activation.
• FXR is a nuclear receptor with multiple effects on
cholesterol, glucose, and bile acid metabolism.
• Bile acids are natural ligands of the FXR.
• The drug may also impair glucose absorption.
39Dr. Aditi M. Panditrao
40. Bile Acid Sequestrants (contd.)
• Three tablets twice a day before lunch and dinner or
six tablets prior to the patient’s largest meal
• Absorption – in trace amounts. Distribution only in GI
tract
• Excretion – Feces
• Side effects – constipation, dyspepsia, abdominal
pain, and nausea.
40Dr. Aditi M. Panditrao
41. Bromocriptine
• Dopamine (D2) agonist
• Acts on the hypothalamic dopaminergic
control of the circadian rhythm of hormone
(GH, prolactin, ACTH, etc.) release and reset it
to reduce insulin resistance
• Taken with food in the morning within two
hours of awakening
41Dr. Aditi M. Panditrao
42. SGLT-2 Inhibitors
• Sodium-Glucose Co-Transporter (SGLT2) is responsible for
most renal glucose reabsorption in the kidney.
• SGLT2 Inhibitors reduce the absorption of glucose in the
kidney, so reduce the blood sugar.
• Canagliflozin and Dapagliflozin
• The urine will test positive for glucose while on this
medication.
• Effectiveness depends on kidney function.
• There is a risk of genital infections and urinary tract infections.
42Dr. Aditi M. Panditrao
48. Newer Drugs (contd.)
• Amylin Analog
• Pramlintide –
• Synthetic Antihyperglycemic drug
• Suppresses glucagon release via undetermined
mechanisms, delays gastric emptying, and has central
nervous system mediated anorectic effects
• Injected subcutaneously prior to meals.
• Plasma t1/2 of 50 minutes.
• Metabolism and clearance is primarily by the kidney
• Useful in both type 1 and 2 DM
• S/E - hypoglycemia and gastrointestinal symptoms,
including nausea, vomiting, and anorexia
48Dr. Aditi M. Panditrao
49. Management of DM
• Non-pharmacological
• Diet
• Exercise
• Pharmacological
• Type 1 – Insulin
• Type 2 – Oral, Insulin
49Dr. Aditi M. Panditrao
50. Status of OHA
• Oral hypoglycemics are indicated only in type 2
diabetes, in addition to diet and exercise.
• They are most effective in patients with—
• Age above 40 years at onset of disease.
• Obesity at the time of presentation.
• Duration of disease < 5 years when starting treatment.
• Fasting blood sugar < 200 mg/dl.
• Insulin requirement < 40 U/day.
• No ketoacidosis or a history of it, or any other
complication.
50Dr. Aditi M. Panditrao
51. Treatment of Type 2 Diabetes
Diagnosis
Therapeutic Lifestyle Change
Combination Therapy - Oral Drug with Insulin
Combination Therapy - Oral Drugs Only
Monotherapy
51Dr. Aditi M. Panditrao
52. Need for Combination
• Failure to maintain a good response to - owing
to a progressive decrease in beta-cell mass
• Reduction in physical activity, decline in lean
body mass, or increase in ectopic fat
deposition
52Dr. Aditi M. Panditrao
56. Recent
• Intravenous Glyburide
• As a treatment for acute stroke, traumatic brain
injury and spinal cord injury
• Based on the identification of a non-selective ATP-
gated cation channel which is upregulated in
neurovascular tissue during these conditions and
closed by sulfonylurea agents
56Dr. Aditi M. Panditrao
57. Recent
• Resveratrol –
• Natural compound found in grape skin
• Improves insulin action, increases insulin
stimulated glucose uptake
• Activation of gene Sirtuin-1
57Dr. Aditi M. Panditrao
59. References
• American Diabetes Association. Strategies for improving care. Sec. 1. In
Standards of Medical Care in Diabetesd2015. Diabetes Care 2015;38(Suppl.
1):S5–S7
• American Diabetes Association. Classification and diagnosis of diabetes. Sec.
2. In Standards of Medical Care in Diabetes—2015. Diabetes Care
2015;38(Suppl. 1):S8–S16
• Kaveeshwar SA, Cornwall J. The current state of diabetes mellitus in India.
AMJ 2014, 7, 1, 45-48. http//dx.doi.org/10.4066/AMJ.2014.1979
• Yesudian C, Grepstad M, Visintin E, Ferrario A. The economic burden of
diabetes in India: a review of the literature. Globalization and Health.
2014;10(1):80.
• IDF Diabetes Atlas . 6 th edition
• Tandon, Nikhil, Raizada, Nishant. The burden of diabetes in India [internet].
2014 Sep 3; Diapedia 1105045828 rev. no. 8. Available
from:http://dx.doi.org/10.14496/dia.1105045828.8
• DeFronzo Annals of Internal Medicine 1999;131:281-303
• Nathan N Engl J Med 2002; 347:1342-1349
59Dr. Aditi M. Panditrao