This presentation explains pharmacotherapy of Diabetes mellitus including Type I and Type II.

1. Pharmacotherapy of
Diabetes mellitus
Dr. Rupali A. Patil
Associate Professor, Pharmacology Department
GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical
Education & Research, Nashik

2. Contents
• Types of Diabetes
• Types of Diabetes mellitus
• Pathophysiology of Diabetes mellitus
• Pharmacotherapy
• Type 1
• Type 2

3. Difference
D. Insipidus D. Mellitus
Meaning Tasteless Honeyed or sweet
Blood glucose Normal High
Cause ADH Insulin
Insulin Normal Deficiency
Type Central, neurogenic
Nephrogenic
Gestational
Dipsogenic
Type I [IDDM/ Juvenile onset DM]
Type II [NIDDM / Maturity Onset DM]
Treatment Vasopressin, Fluid replacement, low
sodium diet
Insulin, OHA, Diet, Exercise
Diabetes (Greek word: syphon / go through)

4. Diabetes mellitus: Indications
• Symptoms: Hyperglycemia, glycosuria, hyperlipidaemia, negative nitrogen
balance & ketonaemia
• Pathological changes: thickening of capillary basement membrane,
increase in blood vessel wall matrix, & cellular proliferation
• Consequences: Lumen narrowing, atherosclerosis, sclerosis of glomerular
capillaries, retinopathy, neuropathy & peripheral vascular insuffficency
• Causes of pathological changes: Enhanced non-enzymatic glycosylation of
tissue proteins and accumulation of large amounts of sorbitol
• Glycosylated haemoglobin (HbA1c ) – Index of protein glycosylation

5. Diabetes mellitus
STAGES.
•PRE-DIABETICS or Potential diabetics. –
Genetic predisposition.
•Latent diabetics or chemical diabetics –
normal F & PP BSL but increased after stress.
• Clinical diabetics – C/F without complications.
• Complicated diabetics.
TYPES .
PRIMARY DM – cause not known.
IDDM NIDDM
SECONDARY DM – due to Pathological
conditions : pancreatitis, cystic fibrosis,
Acromegaly, Cushing syndrome etc.

6. Types of DM
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• Type I—insulin-dependent (IDDM)
– 10% of cases
– Autoimmune destruction of beta cells
– aka juvenile diabetes (age 12)
• Type II—non-insulin dependent (NIDDM)
– Insulin resistance
•Adipocytes secrete resistin?
•Shortage of insulin receptors?
•Heredity, age, obesity
•aka adult onset (age 40)

8. IDDM & NIDDM

9. Pathophysiology of DM
 Hyperglycemia
 Due to decreased peripheral utilization.
 Increased hepatic output of glucose.
 Hypertriglyceridaemia, ketosis
 Less utilization turns it to FFA
 Excess FFA leads to formation of TG & Ketoacidosis.
 Protein catabolism
 Insulin --- Anabolic hormone.
 Promote protein synthesis & inhibit proteolysis.

10. Hyperglycaemia
 Glycosuria
 Glucose in urine above 180 mg/100ml.
 Polyuria (osmotic diuresis), loss of electrolyte, cellular dehydration,polydipsia,
increased caloric loss, Polyphagia, loss of body weight.
 Impaired Phagocytic function
 Hyperosmolar effect (above 375 mOsm/kg)
 Glycosylation of proteins
 Hemoglobin (HbA1c )
 Tissue proteins – Diabetic Nephropathy, D. Neuropathy, D. Retinopathy.

11. Hypertriglyceridemia, Ketosis
 Hypertriglyceridemia
 Glucose converted to FFA
 FFA to TG.
 Increase secretion of VLDL &
chylomicrons.
 Leads to
hypercholesterolemia.
• Ketosis
 Cellular dehydration.
 Ketoacidosis.
 Dyspnoea, Kussmaul breathing.
 Breath acetone smell.
 Electrolyte loss
 Hypovolaemia & hypotension
 Coma & death

12. Protein catabolism
 Protein catabolism increased & anabolism suppressed
 Protein depletion
 Muscle wasting
 Negative nitrogen balance
 Release of large amount of amino acids
 Used for energy production.
 Substrate for enhanced gluconeogenesis.

13. Clinical features
 Cardinal symptoms – Polyuria,
Polyphagia, polydipsia, weight loss.
 Biochemical – Hyperglycemia,
glycosuria, ketosis, ketonuria,
ketoacidosis.

14. Complications.
• Predisposition to infection–
Phagocytic function, protein depletion
• Acute complication–ketotic coma,
Non-ketotic Hyperosmolar coma.
• Chronic complication– atherosclerosis,
Hyperlipidemia, hypercholesterolemia,
• Microangiopathy– D. retinopathy,
nephropathy, neuropathy.

15. Diagnosis
 Urine examination for Glycosuria – exclude renal Glycosuria.
 Urine examination for ketone bodies – other causes
starvation, fasting, high fat diet, repeated vomiting.
 Blood glucose levels – fasting (70-120 mg%) &
postprandial (120-180mg%)
 Glucose tolerance tests (GTT)

16. Glucose tolerance tests (GTT)
• Prior test normal carbohydrate diet for 3 days.
• Early morning fasting BSL & urine taken.
• 75 mg glucose dissolve in 300 ml of water given orally.
• BSL & urine tested ½ hourly for next 3 hrs.

17. Pharmacotherapy
IDDM : Insulin must be injected or inhaled
NIDDM : Food control, exercise, &
medicines:
i) Which increase the sensitivity of target organs to insulin;
ii) Which decrease glucose absorption.

18. Management of Diabetes Mellitus
 Goals of therapy
 Maintain blood glucose to normal.
 Maintain ideal body weight.
 Symptoms free.
 Retard or prevent complications.
 Treatment modalities
 Dietary management.
 Oral hypoglycemic agents.
 Insulin along with dietary management.

19. Treatment modalities
• Dietary management
• Low energy weight reducing diet (for obese NIDDM)
• Weight maintenance diet (Non obese NIDDM)
• Frequent small meals
• Oral hypoglycemic agents
• Sulphonyl urea
• Biguanides
• Insulin along with dietary management.
• For IDDM
• For new Ketoacidosis.
• Emergencies with IDDM & NIDDM

20. Pharmacotherapy :Type 1 DM
• Insulin
• Oral hypoglycemic agents
• Exercise
• Diet
• Pancreas transplant
• Other medications
• High blood pressure medications: ACE inhibitors, Angiotensin Receptor Blockers
• Aspirin
• Cholesterol-lowering drugs

21. Types
• Rapid-acting insulin.
• Short-acting insulin.
• Intermediate-acting insulin.
• Mixed insulin.
• Long-acting insulin.
Insulin

22. Preparations of Insulin
 Classically – produced from beef and pork pancreas
 Contains 1% (10, 000 ppm) other proteins – proinsulin, polypeptides, pancreatic
proteins etc.) – potentially antigenic
 Replaced with highly purified pork/beef insulin/recombinant human insulin
/insulin analogues
 Single peak and Monocomponent insulin (MC)– proinsulin <10 ppm – stable, less
resistance & lipodystrophy
 Unitage/Assay: I U reduces fasting rabbit blood sugar by 45 mg/dl or potency to
induce hypoglycaemic convulsion in mice
 1 mg of International Standard of Insulin = 28 units
 Radioimmunoassay or enzyme immunoassay

23. Types of preparations – Regular (Soluble) Insulin
 Buffered neutral pH solution unmodified insulin stabilized by small amount of
zinc
 Forms hexamers around zinc ions – released slowly & gradually by dilution on SC
administration
 Peak onset 2- 3 hours and lasts for 6-8 hours
 Drawbacks:
 Before meals – early postprandial hyperglycaemia and late post prandial
hypoglycaemia – injected ½ to 1 hour before
 Do not provide basal level of action – interdigestive period
 Slow onset of action is not applicable for IV injection
 Long acting – modified or retard preparations

24. Insulin preparations - Purified
 Rendered insoluble - complexed with protamine or excess zinc
 Lente (Insulin-zinc suspension): 2 types
 Ultrelente: Large particle size, crystalline & insoluble in water– long acting
Semilente: Small particle size, amorphous – short acting; Lente: 7:3 ratio mixture
 Isophane (Neutral Protamine Hagedorn or NPH) insulin: Protamine added just
sufficient to complex all insulin molecules
 Neither are in free form – neutral pH
 On injection: dissociate slowly intermediate action
 Used in combination with regular insulin in 70:30 ratio or 50:50
 Injected twice daily before breakfast & dinner (split-regimen)
 Available preparations: Highly purified MC pork regular insulin, highly purified MC pork
lente, Highly purified MC NPH, highly purified regular insulin & Isophane (30:70 ratio)

25. Human Insulin
• Same amino acid sequence as human insulin - produced by recombinant
DNA technology
• In Escherichia coli – proinsulin recombinant bacteria (prb) and in yeast –
precursor yeast recombinant (pyr) or by enzymatic modification of porcine
insulin
• Human actrapid (regular insulin) – 40 U/ml
• Human monotard (lente), human insulatard (NPH), Human mixtard (30:50),
Insuman (50:50)
• Advantages: More water soluble & hydrophobic, more rapid absorption than
porcine or bovine, more defined peak, shorter duration of action

26. Insulin analogues
• Recombinant DNA technology, modified pharmacokinetic – greater stability &
consistency
• Insulin lispro: Reversing Proline and lysine at B 28 and B 29 position – quick
acting, just before meals
• Insulin aspart: B 28 is replaced by aspartic acid – mimics physiological insulin
• Insulin glulisine: Replacing aspartic acid at B 23 by lysine and glutamic acid
replacing lysine at B 29 – continuous SC insulin infusion (CSII)
• Insulin glargine: Long- acting – precipitates at neutral pH on SC injection –
depot created – slow dissociation – 24 hours low blood level – usually at bed
time

27. Uses of Insulin
• Purpose: Restore metabolism to normal, avoid symptoms due to hyperglycaemia
& glycosuria & prevent complications
• Indications: Type 1 DM, Post-pancreatectomy diabetes and gestational diabetes;
Type 2 DM: Not conrolled by diet and exercise, failure of oral hypoglycaemics,
under wight, tide over crisis and complications (ketoacidosis)
• Treatment: According to requirement and convenience of each patient – by
testing urine & blood glucose level
• Type 1: usually 0.4 to 0.8 U/kg/day (severity and obesity)
• Target: obtain basal control – no single daily dose of long/intermediate/short
acting ones can fulfill
• Multiple (2 – 4) injections daily of long and short acting or Long acting with
Oral hypoglycaemics (meal time)
• Conventionally, s p lit-m ixed regime: mixture of regular with lente/isophane
(30:70 or 50;50) – before breakfast & before dinner

28. Uses of Insulin – contd.
• Basal bolus regime: 3 - 4 daily injections - a long acting (glargine) insulin
before breakfast or before bed time with 2-3 meal time injections of short
rapidly acting (lispro or aspart)
• Other uses: Diabetic Ketoacidosis (Coma), Hyperosmolar (non-ketotic
hyperglycaemic) coma
• Insulin resistance: Type 2 DM, Age, large body fats, pregnancy, OCPs –
acromegally, Cushing`s syndrome, phaeochromocytoma etc.
• Acute Insulin resistance: Infection, trauma, surgery, stress etc.
• Newer Insulin Delivery devices: Insulin syringe, Pen devices, inhalled insulin,
Insulin pumps (CSII) etc.

29. Summary of Insulin preparations
• Short acting: Regular soluble insulin – clear appearance; 6-8 hours – can be
mixed with others except glargine
• Intermediate acting: Lente, NPH or Isophane – cloudy; 20-24 hours - Regular
• Long acting: Glargine and detemir – clear; 24 hours – cannot be mixed with
others (can be combined)
• Rapid acting: lispro, aspart, glulisine – clear; 3-5 hours – can be mixed with
Regular and NPH

31. Reactions and Drug Interactions (DIs)
• HYPOGLYCAEMIA: Labile diabetics
• Causes: Injection of large doses, missing a meal after injection, vigorous exercise
• Symptoms: Sweating, anxiety, palpitation, tremor – counter regulatory; dizziness,
headache, behavioural changes, visual disturbances, hunger, fatigue, weakness,
muscular incoordination etc.- due to deprivation- Below < 40 mg/dl– seizure & coma
• Treatment: Glucose orally and IV – Glucagon – 0.5 to 1 mg IV
• Local reactions (swelling), lipodystrophy, Allergy, Oedema
• Drug Interactions: Beta blockers (beta-2; prolong hypoglycaemia), Thiazides, diuretics,
steroids, OCPs (raises blood sugar), acute alcohol ingestion (hypoglycaemia – glycogen
depletion), Lithium & aspirin (hypoglycaemia – enhance insulin secretion)

32. Adverse reactions
Insulin allergy : Itching, redness, swelling, anaphylaxis shock, Hypoglycemia.
Nausea, hungry, tachycardia, sweating, and tremulousness.
Insulin resistance :
i) Acute : Diabetic ketoacidoisis, Nonketotic hyperosmolar coma.
ii) Chronic :
Microvascular disease: impotence & poor wound healing
Atherosclerosis : Strokes, coronary heart disease
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35. Insulin devices
• Insulin pens
• Continuous Subcutaneous Insulin Infusion (Insulin Pumps)
• Closed Loop Systems

36. Continuous Subcutaneous Insulin
Infusion (Insulin Pumps)

37. Closed Loop Systems

38. Closed loop system with artificial pancreas

40. Insulin prefilled syringe
Insulin pump

43. BREAK

44. Causes ofType 2 DM

45. Type 2 DM

47. Pharmacotherapy :Type 2 DM (NIDDM)

48. Treatment guide forType 2 DM

49. Oral Hypoglycemic Agents
(OHA)

50. Oral Hypoglycemic Agents
Classification
• Secretagogues: increase insulin secretion from beta cells
• Sulfonylureas
• Meglitinides / D- Phenylalanine Derivatives)
• Glucagon-like peptide-1 (GLP-1) receptor agonists
• Dipeptidyl peptidase-4 (DPP-4) inhibitors
• Thiazolidinediones
• Biguanides
• a-glucosidase inhibitors: slow the digestion and absorption of starch and disaccharides
in insulin resistance

51. Classification…………..
• Incretin-based therapies: control post-meal glucose, increasing insulin
release & decreasing glucagon secretion
• Amylin analog: decreases post-meal glucose levels and reduces appetite
• A bile acid-binding sequestrant: decrease in hepatic glucose output

52. Sulfonylureas (KATP Channel blockers)
• 1st generation: Tolbutamide, Tolazamide, Chlorpropamide
• 2nd generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride
• 3rd generation: Glyclazipe
▪ Sulfonylureas
▪ Thiazolidinediones
▪ Biguanides
▪ α-glucosidase inhibitors
▪ Meglitinides

53. Hypoglycemic Mechanism
Rapid mechanism:
Stimulation of insulin secretion
Sulfonylurea receptor in β-cell membrane activated
ATP-sensitive K+-channel inhibited -- Cellular membrane depolarized
Ca2+ entry via voltage-dependent Ca2+ channel
Insulin release
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54. Sulphonylureas
SUR: SU receptors

55. Figure: Control of insulin release from the pancreatic beta cell by glucose & sulfonylureas

56. Pharmacological effects:
• Hypoglycemic effect
• Anti-diuretic effect: chlorpropamide & glybenclamide
• Anti-platelete aggregation effect: glyclazipe
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57. Long term profit involved mechanism:
▪ Inhibition of glucagon secretion by pancreatic α cells;
▪ Ameliorating insulin resistance
▪ Increase insulin receptor number & the affinity to insulin
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58. Pharmacokinetics:
• Well absorbed orally,
• 90% or more bound to plasma proteins
• low volumes of distribution
• May produce active metabolite
• Metabolites are excreted in urine

59. Clinical use:
1. Type 2 diabetes mellitus
2. Diabetes insipidus-- chlorpropamide
Adverse reactions:
1. Gastrointestinal disorders
2. Allergy
3. Hypoglycemia
Chlorpropamide forbidden for ageds & patients with
functional disorder in liver or kidney.
4. Granulocytopenia, cholestasis & hepatic injury

60. Drug interactions
Drugs enhancing SU action (may precipitate hypoglycaemia) are
(a) Displace from protein binding:
Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides
(b) Inhibit metabolism/excretion:
Cimetidine ketoconazole, sulfonamides, warfarin, chloramphenicol
Acute alcohol intake (hypoglycaemia).
(c) Synergise with or prolong pharmacodynamic action:
Salicylates, propranolol (cardio-selective 1 blockers are less liable),
sympatholytic antihypertensives, lithium, theophylline, alcohol (by
inhibiting gluconeogenesis).

61. Drugs decreasing SU action (vitiate diabetes control)
(a) Induce metabolism:
Phenobarbitone, phenytoin, rifampicin, chronic alcoholism.
(b) Opposite action/suppress insulin release:
Corticosteroids, thiazides, furosemide, oral contraceptives

62. Meglitinide/phenylalanine analogues
• Quick and short lasting insulinemic action. Act like SUs.
• Repaglinide:
• Normalises meal-time glucose excursions
• Administered before each major meal to control postprandial hyperglycaemia
Side effects : mild headache, dyspepsia, arthralgia and weight gain
Use: Selected type 2 diabetics who suffer pronounced post-prandial hyperglycaemia, or
to supplement metformin/long-acting insulin
• Nateglinide:
• Stimulates the 1st phase insulin secretion by closing β cell K-ATP channels resulting
• in faster onset & shorter lasting hypoglycaemia than repaglinide.
• Side effects : dizziness, nausea, flu like symptoms and joint pain.

63. Glucagon-like peptide-1 (GLP-1) receptor agonists /
Incretin mimetics and related drugs
• Injectable drugs
• Exenatide is a synthetic version of exendin-4, a peptide found in the saliva of the Gila
monster (a lizard that presumably evolved this as means to disable its prey by
rendering them hypoglycaemic).
• Mimics the effects of GLP-1, but is longer acting, not absorbed by the gut;
administered sc; much more stable than GLP-1.
• Use: In Type 2 diabetes, once weekly injection, used in combination with metformin
& a sulfonylurea in poorly controlled obese patients.
• Associated with modest weight loss. Reduces hepatic fat accumulation .
• Adverse effects: hypoglycemia, GI-disturbances, pancreatitis

64. Liraglutide:
• An alternative injectable GLP-1 agonist.
• Lower blood glucose after a meal by increasing insulin secretion, suppressing
glucagon secretion & slowing gastric emptying.
• They reduce food intake.

65. Dipeptidyl peptidase-4 (DPP-4) inhibitors/ Gliptins
• Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin
• Synthetic drugs; competitively inhibit DPP-4-- lower blood glucose by potentiating
endogenous incretins (GLP-1 and GIP, which stimulate insulin secretion).
• Do not cause weight loss or weight gain.
• Absorbed from the gut & administered once (or, in the case of vildagliptin, twice)
daily by mouth. Eliminated partly by renal excretion & metabolised by hepatic CYP
enzymes.
• Well tolerated with a range of gastrointestinal adverse effects; occasional liver
disease, worsening of heart failure & pancreatitis.
• May act as tumour promoters.
• Use: Type 2 diabetes in addition to other oral hypoglycaemic drugs

66. Thiazolidinediones / PPARg activator
▪ Pioglitazone, troglitazone, ciglitazone, rosiglitazone (MI, CHF)
▪ Pharmacological effects:
• Improving function of pancreas β cells.
• Ameliorating insulin resistance byenhancing GLUT4 expression & translocation
• Suppression of hepatic gluconeogenesis
• Activation of genes regulating fatty acid metabolism & lipogenesis in adipose
tissue insulin sensitizing action
• Reduction in Lipolysis and plasma fatty acid levels
20

67. ▪ Mechanism (possible):
Peroxisome proliferator-activated receptor-γ (PPAR-γ) activated
Nuclear genes involved in glucose & lipid metabolism & adipocyte
differentiation activated
▪ Clinical use:
Insulin resistance & type 2 diabetes mellitus
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68. Biguanides / AMPK activator
• Metformin
• Present in French lilac, Galega officinalis, used to treat diabetes in traditional medicine for centuries
• Drug of first choice in Type 2 DM
• Mechanism of action: exact mechanism not known.
• Biochemical actions:
1. Suppresses hepatic gluconeogenesis & glucose output from liver.
2. Enhances insulin-mediated glucose uptake & disposal in skeletal muscle & fat.
• glycogen storage in skeletal muscle
• reduced lipogenesis in adipose tissue and enhanced fatty acid oxidation.
3. Interferes with mitochondrial respiratory chain & promotes peripheral glucose
utilization through anaerobic glycolysis.
4. Reduces circulating LDL & VLDL

69. Pharmacokinetics:
• Clearance of metformin approximates GFR.
• It accumulates in renal failure & increases the risk of lactic acidosis.
Side effects:
• Lactic acidosis: contraindicated in hypotensive states, heart failure, severe
respiratory, hepatic & renal disease, in alcoholics
• Vit B12 deficiency: due to interference with absorption with high dose
• Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea &
tiredness

70. a-Glucosidase inhibitors
Acarbose
• Reduces carbohydrate absorption; it causes flatulence & diarrhoea.
• Delays carbohydrate absorption, reducing the postprandial increase in blood glucose.
• Adverse effects : related to its main action & consist of flatulence, loose stools or
diarrhoea, & abdominal pain & bloating.
• Use: Helpful in obese type 2 patients inadequately controlled by diet with / without
other agents. Can be co-administered with metformin.
Miglitol :
• Smaller molecule than acarbose, & it is a stronger inhibitor of sucrase.
• Potency for other a-glucosidases is equivalent to acarbose.
• Absorption is substantial, but variable. Absorbed drug is excreted by the kidney.
Voglibose: similar to acarbose

71. Amylin analogue:
• Amylin / ‘islet amyloid polypeptide’ (IAP) : produced by pancreatic b-cells
• Acts in the brain to reduce glucagon secretion from a-cells, delay gastric emptying,
retard glucose absorption and promote satiety
• Decreases post-meal glucose levels and reduces appetite
Pramlintide
• It is a synthetic amylin analogue which on s.c. injection before meal attenuates
postprandial glycaemia & exerts a centrally mediated anorectic action.
• The duration of action is 2–3 hours.
• Used as an adjuvant to meal time insulin injection to suppress the glycaemic peak in
both type 1 & type 2 diabetics.
• Reduction in body weight is an additional benefit.

72. Dopamine-D2 receptor agonist
Bromocriptine
• A quick release oral formulation approved by US-FDA for adjunctive treatment of type 2 DM.
• Taken early in the morning it is thought to act on the hypothalamic dopaminergic control of
the circadian rhythm of hormone (GH, prolactin, ACTH, etc.) release & reset it to reduce
insulin resistance.
• Can be taken alone to supplement diet + exercise or added to metformin or SU or both.
• Marginally improves glycaemic control & lowers HbA1c by upto 0.5%

73. Sodium-glucose cotransport-2 (SGLT-2) inhibitor
• Glucose filtered at the glomerulus is reabsorbed in the proximal tubules.
• The major transporter which accomplishes this is SGLT-2, whose inhibition induces
glucosuria & lowers blood glucose in type 2 DM, as well as causes weight loss.
Dapagliflozin:
• Single daily dose : produces round-the-clock glucosuria & lowers blood glucose levels.
• Side effects: glycosuria which can predispose to urinary & genital infections,
electrolyte imbalance & increased urinary frequency.
• Tolerability and safety not established.

74. POTENTIAL NEW ANTIDIABETIC DRUGS
• α2-adrenoceptor antagonists,
• Inhibitors of fatty acid oxidation,
• Activators of glucokinase,
• β3 agonists : control lipolysis in fat cells, currently in development, in the
treatment of obese patients with type 2 diabetes.

76. Summary

77. Diabetic complications
• Diabetic neuropathy
• Diabetic nephropathy
• Diabetic retinopathy

78. Diabetic complications

79. Neuropathy

83. Management of diabetic complications
1. Make a commitment to managing your diabetes
2. Don't smoke
3. Blood pressure and cholesterol control
4. Regular physicals and eye exams
5. Vaccines up to date: Flu vaccine, Pneumonia vaccine, Hepatitis B vaccine
6. Care of teeth
7. Feet care
8. Daily aspirin
9. Alcohol intake
10. Reduce stress

84. Thank you!!!