This document provides definitions and classifications of diabetes mellitus. It discusses the pathogenesis of type 1 and type 2 diabetes, focusing on genetic and environmental factors. Complications of diabetes are described, including acute metabolic issues like DKA and chronic issues like atherosclerosis, nephropathy, neuropathy and retinopathy. Diagnosis methods such as blood glucose testing and oral glucose tolerance tests are outlined. Gestational diabetes is also briefly discussed.

1. Diabetes mellitus
DR KAMALESH LENKA

2. DEFINATION
• As per the WHO, diabetes mellitus (DM) is defined as a
heterogeneous metabolic disorder characterised by common feature
of chronic hyperglycaemia with disturbance of carbohydrate fat and
protein metabolism

3. Classification

4. The vast majority of cases of diabetes fall into one
of two broad classes:
• Type 1 diabetes is an autoimmune disease characterized by pancreatic
β-cell destruction and an absolute deficiency of insulin.
• Type 2 diabetes is caused by a combination of peripheral resistance to
insulin action and an inadequate secretory response by the pancreatic
β cells (“relative insulin deficiency)

5. Normal Insulin Physiology and Glucose
Homeostasis

6. • Normal glucose homeostasis is tightly regulated by three interrelated
processes:
• (1) glucose production in the liver;
• (2) glucose uptake and utilization by peripheral tissues, chiefly skeletal
muscle; and
• (3) the actions of insulin and counterregulatory hormones (especially
glucagon
• The principal function of insulin is to increase the rate of glucose
transport into certain cells in the body

8. Pathogenesis of Type 1 Diabetes
• The basic phenomenon in type 1 DM is destruction of β-cell mass,
usually leading to absolute insulin deficiency.
• type 1A DM is explained on the basis of 3 mutually-interlinked
mechanisms:
• genetic susceptibility,
• autoimmunity,
• certain environmental factors

9. Genetic susceptibility
• It has been observed in identical twins that if one twin has type 1A
DM, there is about 50% chance of the second twin developing it, but
not all
• About half the cases with genetic predisposition to type 1A DM have
the susceptibility gene located in the HLA region of chromosome 6
(MHC class II region), particularly HLA DR3, HLA DR4 and HLA DQ
locus.

10. Autoimmunity
• Presence of islet cell antibodies against GAD (glutamic acid
decarboxylase), insulin etc,
• Occurrence of lymphocytic infiltrate in and around the pancreatic
islets termed insulitis. It chiefly consists of CD8+ T lymphocytes with
variable number of CD4+ T lymphocytes and macrophages.
• Selective destruction of β-cells while other islet cell types (glucagon-
producing alpha cells, somatostatin-producing delta cells, or
polypeptide-forming PP cells remain unaffected

11. • Role of T cell-mediated autoimmunity
• Association of type 1A DM with other autoimmune diseases in about
10-20% cases such as Graves’ disease, Addison’s disease, Hashimoto’s
thyroiditis, pernicious anaemia
• Remission of type 1A DM in response to immunosuppressive therapy
such as administration of cyclosporine A.

12. Environmental factors
• Certain viral infections-e.g. mumps, measles, coxsackie B virus,
cytomegalovirus and infectious mononucleosis.
• Experimental induction of type 1A DM with certain chemicals-alloxan,
streptozotocin and pentamidine.
• Geographic and seasonal variations-incidence suggest some common
environmental factors.
• Possible relationship of early exposure to bovine milk proteins

14. PATHOGENESIS OF TYPE 2 DM
• The basic metabolic defect in type 2 DM is
• either a delayed insulin secretion relative to glucose load (impaired
insulin secretion),
• or the peripheral tissues are unable to respond to insulin (insulin
resistance)
• Type 2 DM is a heterogeneous disorder with a more complex etiology
and is far more common

15. Genetic factors
• Genetic component has a stronger basis for type 2 DM than type 1A
DM
• There is approximately 80% chance of developing diabetes in the
other identical twin if one twin has the disease.
• A person with one parent having type 2 DM is at an increased risk of
getting diabetes, but if both parents have type 2 DM the risk in the
offspring rises to 40%.

16. Constitutional factors
• Certain environmental factors such as
• obesity
• hypertension
• level of physical activity
• play contributory role and modulate the phenotyping of the disease

17. Insulin resistance
• Resistance to action of insulin impairs glucose utilisation and hence
hyperglycaemia
• There is increased hepatic synthesis of glucose
• Hyperglycaemia in obesity is related to high levels of free fatty acids
and cytokines (e.g. TNF-α and adiponectin) affect peripheral tissue
sensitivity to respond to insulin

18. • Currently, it is proposed that insulin resistance may be possibly due to
one of the following defects
• Polymorphism in various post-receptor intracellular signal pathway
molecules.
• Elevated free fatty acids seen in obesity may contribute e.g. by
impaired glucose utilisation in the skeletal muscle, by increased
hepatic synthesis of glucose, and by impaired β-cell function

19. • Insulin resistance syndrome-
• complex of clinical features occurring from
• insulin resistance and
• its resultant metabolic derangements that includes hyperglycaemia
and compensatory hyperinsulinaemia.

20. • The clinical features are in the form of accelerated cardiovascular
disease and may occur in both obese as well as non-obese type 2 DM
patients
• features include
• mild hypertension
• Dyslipidaemia

21. Impaired insulin secretion
• in response to insulin resistance there is compensatory increased
secretion of insulin (hyperinsulinaemia) in an attempt to maintain
normal blood glucose level.
• Eventually, however, there is failure of β-cell function to secrete
adequate insulin

22. Increased hepatic glucose synthesis
• In type 2 DM, as a part of insulin resistance by peripheral tissues, the
liver also shows insulin resistance
• i.e. in spite of hyperinsulinaemia in the early stage of disease,
gluconeogenesis in the liver is not suppressed.

26. COMPLICATIONS OF DIABETES
• I. ACUTE METABOLIC COMPLICATIONS-
• 1. Diabetic ketoacidosis (DKA)-
• Almost exclusively a complication of type 1 DM.
• can develop in patients with severe insulin deficiency combined with
glucagon excess.
• Failure to take insulin and exposure to stress are the usual
precipitating causes.
• Severe lack of insulin causes lipolysis in the adipose tissues, resulting
in release of free fatty acids into the plasma.

27. • These free fatty acids are taken up by the liver where they are
oxidised through acetyl coenzyme-A to ketone bodies, principally
acetoacetic acid and β-hydroxybutyric acid.
• Clinically, the condition is characterised by anorexia, nausea,
vomitings, deep and fast breathing, mental confusion and coma.

28. • Hyperosmolar hyperglycaemic nonketotic coma (HHS)-usually a
complication of type 2 DM
• It is caused by severe dehydration resulting from sustained
hyperglycaemic diuresis
• Blood sugar is extremely high and plasma osmolality is high.
• Thrombotic and bleeding complications are frequent due to high
viscosity of blood

29. • Hypoglycaemia-It may result from
• excessive administration of insulin,
• missing a meal,
• or due to stress.
• Hypoglycaemic episodes are harmful as they produce permanent
brain damage, or may result in worsening of diabetic control and
rebound hyperglycaemia, so called Somogyi’s effect.

31. LATE SYSTEMIC COMPLICATIONS

32. • Atherosclerosis-
• often associated with complicated plaques such as
• ulceration
• Calcification
• Thrombosis
• but possible contributory factors for atherosclerosis are
• Hyperlipidaemia
• reduced HDL levels

33. • The possible ill-effects of accelerated atherosclerosis in diabetes are
• early onset of coronary artery disease,
• silent myocardial infarction,
• cerebral stroke and
• gangrene of the toes and feet.
• Gangrene of the lower extremities is 100 times more common in
diabetics than in non-diabetics.

34. • Diabetic microangiopathy-
• Microangiopathy of diabetes is characterised by basement membrane
thickening of small blood vessels and capillaries of different organs
and tissues
• Similar type of basement membrane-like material is also deposited in
nonvascular tissues such as peripheral nerves, renal tubules and
Bowman’s capsule.

35. • The pathogenesis of diabetic microangiopathy as well as of peripheral
neuropathy in diabetics is believed to be due to recurrent
hyperglycaemia that causes increased glycosylation of haemoglobin
and other proteins (e.g. collagen and basement membrane material)
resulting in thickening of basement membrane

36. • Diabetic nephropathy-types of lesions are described in diabetic
nephropathy
• i) Diabetic glomerulosclerosis which includes diffuse and
• nodular lesions of glomerulosclerosis.
• ii) Vascular lesions that include hyaline arteriolosclerosis of
• afferent and efferent arterioles and atheromas of renal arteries.
• iii) Diabetic pyelonephritis and necrotising renal papillitis.
• iv) Tubular lesions or Armanni-Ebstein lesion.

37. • Diabetic neuropathy-
• Diabetic neuropathy may affect all parts of the nervous system but
symmetric peripheral neuropathy is most characteristic.
• changes are segmental demyelination, Schwann cell injury and axonal
damage

38. • Diabetic retinopathy-
• There are 2 types of lesions involving retinal vessels:
• background
• proliferative
• Infections-Diabetics have enhanced susceptibility to various infections such as
• tuberculosis,
• pneumonias,
• pyelonephritis,
• otitis,
• carbuncles
• diabetic ulcers

39. Diagnosis
• According to the American Diabetes Association (ADA) and the World
Health Organization (WHO), diagnostic criteria for diabetes include
the following:
• A fasting plasma glucose greater than or equal to 126 mg/dL, and/or
• A random plasma glucose greater than or equal to 200 mg/dL (in a
patient with classic hyperglycemic signs, discussed later), and/or
• A 2-hour plasma glucose greater than or equal to 200 mg/dL during
an oral glucose tolerance test with a loading dose of 75 gm, and/or
• A glycated hemoglobin (HbA1C) level greater than or equal to 6.5%
(glycated hemoglobin is further discussed under chronic
complications of diabetes)

40. Impaired glucose tolerance (prediabetes) is
defined as:
• A fasting plasma glucose between 100 and 125 mg/Dl (“impaired
fasting glucose”), and/or
• A 2-hour plasma glucose between 140 and 199 mg/dL during an oral
glucose tolerance test, and/or
• HbA1C level between 5.7% and 6.4%

41. • 1. Glucosuria Benedict’s qualitative test
• Renal glucosuria -After diabetes, the next most common cause of
glucosuria is the reduced renal threshold for glucose. In such cases
although the blood glucose level is below 180 mg/dl (i.e. below
normal renal threshold forglucose) but glucose still appears regularly
and consistently in the urine due to lowered renal threshold
• benign condition unrelated to diabetes and runs in families and may
occur temporarily in pregnancy without symptoms of diabetes.

42. • Alimentary (lag storage) glucosuria-rapid and transitory rise in blood
glucose level above the normal renal threshold may occur in some
individuals after a meal
• During this period, glucosuria is present

43. • Ketonuria-
• Rothera’s test (nitroprusside reaction) and strip test are conveniently
performed for detection of ketonuria
• II. SINGLE BLOOD SUGAR ESTIMATION-Currently used
• are O-toluidine, Somogyi-Nelson and glucose oxidase methods
• III.SCREENING BY FASTING GLUCOSE TEST

44. • IV. ORAL GLUCOSE TOLERANCE TEST-
• Oral GTT is performed principally for patients with borderline fasting
plasma glucose value
• The patient who is scheduled for oral GTT is instructed to eat a high
carbohydrate diet for at least 3 days prior to the test and come after
an overnight fast on the day of the test (for at least 8 hours).
• A fasting blood sugar sample is first drawn. Then 75 gm of glucose
dissolved in 300 ml of water is given.

45. • Blood and urine specimen are collected at half-hourly intervals for at
least 2 hours.
• Blood or plasma glucose content is measured and urine is tested for
glucosuria to determine the approximate renal threshold for glucose

47. Gestational diabetes
• Pregnancy is a “diabetogenic” state in which the prevailing hormonal
milieu favors a state of insulin resistance.
• In some euglycemic pregnant women this can give rise to gestational
diabetes
• Women with pregestational diabetes (where hyperglycemia is already
present in the periconception period) have an increased risk for
stillbirth and congenital malformations in the fetus

48. • Therefore, tight glycemic control is needed early in pregnancy to
prevent congenital defects, and through the later trimesters of
pregnancy to prevent fetal overgrowth (macrosomia

49. THE END