DIABETES MELLITUS OVERVIEW, COMPLICATIONS & MANAGEMENT

1. DIABETES
MELLITUS
DEPARTMENT OF GENERAL MEDICINE

2. DEFINITION
Diabetes Mellitus refers to a group of common metabolic disorders
that share the phenotype of hyperglycemia, due to defect in insulin
secretion, insulin action or both.

3. EPIDEMIOLOGY

4. CLASSIFICATION OF DIABETES MELLITUS
COURTESY : WHO

5. PATHOPHYSIOLOGY OF DIABETES
MELLITUS

6. PATHOPHYSIOLOGY
 The body obtains glucose from
three main places:
 The intestinal absorption of food
The breakdown of glycogen, the
storage form of glucose found in the
liver.
 Gluconeogenesis, the generation
of glucose from non-
carbohydrate substrates in the
body.

7. PATHOPHYSIOLOGY
Insulin plays a critical role in balancing glucose
levels in the body:
 It can inhibit the breakdown of glycogen or the
process of gluconeogenesis.
 It can stimulate the transport of glucose into
fat and muscle cells.
 It can stimulate the storage of glucose in the
form of glycogen.

8. GENERAL PHYSIOLOGY

10. Ominous octet of Defronzo
Pancreas
Liver
Intestine
Adipose tissue
Kidneys
Muscle
Brain
1) Decreased insulin secretion
2) Increased alpha cell activity / glucagon
3) Increased gluconeogenesis
4) Increased glucose absorption
5) Increased lipolysis
6) Increased glucose reabsorption
7) Decreased glucose uptake
8) Neurotransmitter dysfunction

11. PATHOPHYSIOLOGY - TYPE 1
Type 1 diabetes mellitus is characterized by loss of the
insulin-producing beta cells of the islets of Langerhans in
the pancreas, leading to insulin deficiency.
 This type can be further classified as immune-mediated
or idiopathic.
 The majority of type 1 diabetes is of the immune
mediated nature, in which a T-cell mediated
autoimmune attack leads to the loss of beta cells
and thus insulin.

12. Williams Textbook of Endocrinology 14th Ed

14. PATHOPHYSIOLOGY – TYPE 2
 A number of lifestyle factors are known to be important to
the development of type 2 DM, including
 Obesity
 lack of physical activity
 poor diet
 Stress
 Dietary factors also influence the risk of developing type 2
DM such as
 sugar-sweetened drinks
 Type of fats in diet
 Saturated fats and trans fatty acids increasing the risk
 Polyunsaturated and monounsaturated fat decreasing the risk
 Eating lots of white rice also may increase the risk of
diabetes.
 A lack of exercise is believed to cause 7% of cases

15. CLINICAL FEATURES

16. DIAGNOSIS
• Criteria for diagnosis :
1. Symptoms of diabetes plus random blood glucose
concentration > 11.1 mmol/L (200 mg/dl) or
2. Fasting plasma glucose > 7mmol/L( 126mg/dl) or
3. HbA1C > 6.5% or
4. 2 hour plasma glucose >11.1 mmol/L (200 mg/dl)
during an oral glucose tolerance test.
ADA GUIDELINES, DIABETES CARE, 2019

17. TREATMENT

18. Management of DM
The major components of the treatment of diabetes are:
Medical Nutrition
Therapy
A
Oral hypoglycemic
therapy
B
InsulinTherapy
C

19. Dietary treatment should aimat:
◦ ensuring weight control
◦ providing nutritional requirements
◦ allowing good glycaemic control with blood glucose
levels as close to normal as possible
◦ correcting any associated blood lipid abnormalities
A. Diet

20. MEAL TIMING AND CONSISTENCY
 Total daily food intake may be distributed
consistently throughout the day as follows:
3 main meals- breakfast, lunch and dinner
2-3 snacks- mid morning, afternoon and bedtime snacks etc.

22. Physical activity promotes weight reduction and improves
insulin sensitivity, thus lowering blood glucose levels.
Adults, with Type 1 & 2 diabetes should engage in 150 min
or more of moderate to vigorous intensity aerobic activity
per week, spread over at least 3 days/week, with no more
than 2 consecutive days without activity.
Exercise

23. TARGETS OF TREATMENT
Factors Target
Blood (capillary plasma)
glucose
Fasting/ pre-meal: 4.4-7.2mmol/L
Post-meal: <10mmol/L
HbA1c <53mmol/mol / 7%
Blood pressure <140/90 mm of Hg
Blood lipids Total cholesterol: < 4mmol/L or
150mg/dl
LDL cholesterol: < 2mmol/L or 75mg/dl
BMI & Waist circumference BMI: <25kg/m2
WC: <90 cm (male)
<80 cm (female)
Patients Teaching, training & empowerment to take
part in treatment
Williams Textbook of Endocrinology 14th Ed

24. MONITORING & CHANGING
TREATMENT REGIME
 Blood glucose testing:
There is usually no need for regular
self-assessment of blood glucose,
unless they are treated with insulin,
or at risk of hypoglycemia while
taking sulphonylureas.
Insulin-treated patients should be taught
how to monitor their own blood glucose
using capillary blood glucose meters.
(SMBG)
Continuous glucose monitoring (CGM)
also has an important role in insulin
treated patients.

25. PHARMACOLOGICAL THERAPY

26. PHARMACOLOGICAL AGENTS
Oral anti-diabetic drugs Parenteral agents
Insulin sensitizers Insulin
Insulin secretogogues Amylin agonists
Thiazolidinediones GLP1 receptor agonists
Alpha glucosidase inhibitors
Incretin mimetics.
SGLT2 inhibitors.
Others.

27. INSULIN SENSITIZERS
Biguanides (Metformin):
 MOA-
reduction of hepatic gluconeogenesis.
slows intestinal absorption of sugars and improves
peripheral glucose uptake and utilization.
Weight loss may occur because metformin causes
loss of appetite.
 Adverse effects
GI upset (modified release preparations)
Lactic acidosis
Vit B12 deficiency
Hepatic and renal disease

28. CONTINUED..
 Contraindications
eGFR of below 30 mL/min.
dose should be halved when eGFR is 30–45
mL/min
Any acute illness
Hypoxic condition(cardiac/pulmonary disease)
Hepatic impairment

29. INSULIN SECRETOGOGUES
Sulphonylureas: Gliclazide,
Glibenclamide,
Glimepiride etc.
 MOA- Sulphonylureas act by
closing the pancreatic β-cell
ATP-sensitive potassium
channel, decreasing K+ efflux,
which ultimately triggers
insulin secretion
 Meglitinide analogues :
Repaglinide, Nateglinide

30. THIAZOLIDINEDIONES
• Rosiglitazone, Pioglitazone
• MOA : Reduce insulin resistance by binding to
PPAR-ɣ nuclear receptor.
• s/e : ↑risk of bladder cancer
• Contraindications : CHF, liver disease, diabetic
macular oedema, pregnancy

31. ALPHA GLUCOSIDASE INHIBITORS
 Acarbose, Voglibose, Miglitol
 MOA- competitively block the action of the intestinal
enzyme alpha-glucosidase which breaks down
oligosaccharides (break down product of starch), and
thus inhibit the complete digestion of carbohydrate.
 Adverse effect :GI upset, flatulence

32. INCRETIN MIMETICS
 Sitagliptin, Vildagliptin , Linagliptin, Saxagliptin,
Teneligliptin
 MOA-
a) I



33. SGLT 2 INHIBITORS
 Dapagliflozin, Canagliflozin,
Empagliflozin
 MOA-
The sodium-glucose cotransporter-2
(SGLT-2) is the main site of reabsorption
of filtered glucose in renal tubules.
SGLT-2 inhibitors inhibit this SGLT-2 in
the proximal tubules, thus reduce the
reabsorption of filtered glucose from the
tubular lumen and lower the renal
threshold for glucose.
 Weight loss
 Reduction in CVS mortality
 Adverse effects: genital fungal
infection, euglycemic ketosis.

34. SELECTION & INITIATION OF A TREATMENT REGIMEN
Williams Textbook of Endocrinology 14th Ed

35. INSULIN THERAPY

36. CONTINUED…
 In type 2 DM, insulin is usually initiated as a once-daily long
acting insulin 10 U/day or 0.1-0.2 U/kg/day, either alone or in
combination with oral hypoglycemic agents.
 Simplest regimen: Twice-daily administration of a short-acting
and intermediate-acting insulin (usually soluble and isophane
insulins). Two-thirds of the total daily requirement of insulin is
given in the morning in a ratio of short-acting to intermediate-
acting of 1 : 2
 Multiple injection regimens (intensive insulin therapy) are
popular, with short-acting insulin being taken before each
meal, and intermediate- or long-acting insulin being injected
once or twice daily (basal-bolus regimen).

37. DOSE CALCULATION OF INSULIN
Three factors are considered here:
 Total Daily Insulin (TDI):
TDI= Weight in pounds / 4 OR 0.4-1 units/kg/day
Half TDI- Short / rapid acting (thrice daily)
Half TDI- Intermediate (twice) / long acting (once daily); If
intermediate is used, 2/3rd in morning & 1/3rd in night.
 Carbohydrate disposal / Intake.
 Blood glucose level correction.

38. SIDE EFFECTS OF INSULIN
THERAPY
• Hypoglycemia
• Weight gain
• Peripheral oedema (insulin treatment causes
salt and water retention in the short term)
• Insulin antibodies
• Local allergy (rare)
• Lipohypertrophy or lipoatrophy at injection
sites.

39. PHARMACOLOGIC THERAPY FOR
TYPE 1 DIABETES
 Multiple daily injections of prandial and basal
insulin, or continuous subcutaneous insulin infusion.
 Consider educating individuals with type 1 diabetes on
matching prandial insulin doses to carbohydrate
intake, pre meal blood glucose levels, and anticipated
physical activity.

40. NEWER COMBINATIONS
• GLP 1 RECEPTOR AGONISTS :
Liraglutide
Semaglutide (oral)
Exenatide
Lixisenatide
Dulaglutide
Albiglutide
• IDegLira – Insulin Degludec & Liraglutide
• IGlarLixi – Insulin Glargine & Lixisenatide

41. EMERGING TREATMENT
MODALITIES
• Once weekly Basal Insulin Icodec
(HL – 196 hrs)
• CGM-Sensor augmented insulin
devices with closed loop systems.
• Glucokinase activators, 11 ßHSD1
inhibitor, GPR40 agonists.
• Whole pancreas transplantation.
• Pancreatic islet cell
transplantation.
• Stem cell derived islet cell
transplantation

42. IS DIABETES REVERSIBLE?
• Technology enabled precision nutrition
• Combination of micro, macro nutrients & biota
• Serial HbA1C monitoring
• Blood glucose prediction
• Detection of adverse glycemic events
• Risk & patient personalisation.

43. COMPLICATIONS

44. COMPLICATIONS
microvascular
Acute
Chronic
macrovascular
neuropathy
nephropathy
retinopathy
Coronary artery disease
Peripheral arterial disease
DKA / HHS
hypoglycemia
Dysglycemia

45. DKA
Joslin’s Diabetic Care : 14th edition

46. 1. Hyperglycemia: of > 300 mg/dl &
glucosuria
2. Ketonemia and ketonuria
3. HAGMA: pH < 7.25, serum bicarbonate <
15 mmol/l. Anion gap >10.
This is usually accompanied with severe
dehydration and electrolyte imbalance.
DIAGNOSIS

47. Investigations
• Plasma glucose > 350
• Hyponatremia
• ABG : HAGMA , pCO2
• Hyperkalemia / hyper phosphatemia
• Plasma Beta hydroxybutyrate
• Urine ketostix
• TLC
• RFT
• ECG / CXR
• CT Brain

48. DKA management
Insulin infusion
Fluid replacement
0.1 u/kg IV bolus f/b
0.15 u/kg/hr for 5 hrs
3 Ltr NS over 3 hrs
3 u/hr for next 5 hr
3 Ltr NS over next 6 hrs
1 u/hr for next 5 hrs and
overlap with S/C insulin
3 Ltr 0.45% NS / 5% D over 12 hrs

49. • Hypokalemia ,
• Once K+<4.0, add 20-40 meq KCL per liter.
• If initial K+ < 2.5 , correct K+ first, then insulin
infusion
• Phosphate deficit
• May want to use K-Phosphate
• Bicarbonate not given unless pH <7 or
bicarbonate <5 mmol/L
Correction of Electrolytes

50. PARAMETERS DKA HHS
PLASMA
GLUCOSE(MG/DL)
250-600 600-1200
ARTERIAL PH 6.8-7.3 >7.3
SERUM BICARBONATE <15 meq/l Normal to slightly ↓
PLASMA KETONES ++++ +/-
ARTERIAL PCO2 20-30 NORMAL
ANION GAP ↑ NORMAL TO SLIGHTLY ↑
SERUM POTASSIUM NORMAL TO ↑ NORMAL
DKA VS HHS

51. .
HYPOGLYCEMIA
• Whipple triad:
1 ) Signs and symptoms consistent with hypoglycemia.
2) Associated low glucose level.
3) Relief of symptoms with supplemental glucose

52. Clinical features
ANS : palpitations, tremor, and anxiety
• sweating, hunger, and paresthesias
CNS : behavioral changes, confusion, fatigue, loss of
consciousness , cognitive impairment, somnolence,
dizziness, slurred speech
• hemiparesis, seizures and death

53. Harrison’s Principles of Internal Medicine, 20th edition

54. Management of Hypoglycemia
The management of hypoglycaemia can be divided into three
phases:
1. acute intervention (25%D, thiamine, glucagon,
hydrocortisone)
2. maintenance therapy inf D5/DNS , octreotide
3. subsequent measures diazoxide, verapamil, drug
modification

55. • Hyperglycemia is found in upto 90% of patients in ICU ,
occurring both in diabetics & non-diabetics
• Hyperglycemia independently increases mortality and
duration of ICU stay
• No “one protocol fits all” guideline available till date.
• Diabetic and non-diabetic patients respond differently
to dysglycemia, experienced in ICU
Dysglycemia in ICU

56. Somogyi & Dawn phenomenon

57. • 100 IU regular Insulin in 100ml 0.9% NS to run IV via
infusion pump and start @ CBG/70 per hour (calculated
to nearest 0.5 IU)
• Give IV bolus @ CBG/70 IU if CBG>180 mg/dl
• Monitor CBG hourly
• Stop infusion when CBG<70
• Give 25g dextrose 50% IV if CBG<50
• Start insulin infusion when CBG>90 @ 0.5 U/hr ,may be
escalated as per CBG
Insulin infusion protocol
Washington’s manual of critical care : 3rd edition

58. Microvascular complications
Skyler J. Diabetic complications: Endocrinol Metab Clin North Am.

59. Diabetic nephropathy
• Risk @ HbA1c > 7
• T1DM 5 yrs / T2DM 20 yrs
Markers :
Homocysteine
Urine ACR
Creatinine Clearance
Williams Textbook of Endocrinology 14th Ed

60. Microscopy
Glomeruli :
•BM thickening
•K-W lesions
•Fibrin caps
Tubules
•Necrotisisng papilitis
Vascular
•arteriosclerosis
Davidson’s principles & practice of medicine, 23rd edition

61. Diabetic retinopathy
Atlas of Clinical Endocrinology. Vol 2: Diabetes. Philadelphia, PA:

62. PDR
Atlas of Clinical Endocrinology. Vol 2: Diabetes. Philadelphia, PA:

63. Diabetic Neuropathy
• DSPN
• Autonomic neuropathy (CVS / GI / GU)
• Mono-Neuritis multiplex
• Entrapment Neuropathy
• Diabetic Amyotrophy
• Polyradiculopathy
American Diabetes Association.
Diabetes Care. 2017;40:

64. Diabetic dermopathy
hutchison’s clinical methods : 2018 Elsevier

65. Infections
• Rhinocerebral
mucosmycoses
• Acute emphysematous
cholecystitis /
pyelonephritis
• Malignant otitis externa
NEJM : sept 2012, vol 38, issue 12

66. DM and lipid profile
• total cholesterol
• N LDL
• VLDL
• TAG
• HDL
• Oxidised LDL

67. Williams Textbook of Endocrinology 14th Ed

69. REFERENCES
 Williams Textbook of Endocrinology 14th Ed
 Davidson’s principles & practice of medicine, 23rd edition.
 American Diabetes Association (ADA); Standards of
Medical Care in Diabetes 2019
 IDF Clinical Practice Recommendations for managing
Type 2 Diabetes in Primary Care (2019)
 Harrison’s Principles of Internal Medicine, 20th edition.