Pathogenesis of Type-2-Diabetes

Pathogenesis of Type-2-Diabetes

Genetic factors: These are of greater importance in type-2-diabetes than in type-1- diabetes. Among the identical twins the concordance rate is above 90%.

            However, like type-1-diabeties it is not HLa associated except a weak link among the Pima Indian.  There is no evidence of autoimmune mechanism except a few subgroups. The mode of inheritance is largely unknown in the maturity onset diabetes which is autosomal dominant and linked to chromosomes 7, 20 and 12. The defect in chromosome has been traced to mutations in gene encoding the glucose phosphorylation enzyme glucokinase which serves as part of glucose sensing mechanism regulating insulin secretion in pancreatic beta cells. There is also evidence that a subgroup of patients with type-2-diabetes between polymorphic alleles of glycogen synthetase which is rate limiting step for glucose conversion to glycogen storage in the muscle cells.

Two metabolic defects that characterize type-2-diabetes are:

1. Derangement of insulin secretion that is insufficient relative to glucose load.
2. An inability of peripheral tissues to respond to insulin (insulin resistance).The primary abnormality of an insulin secreting defect verses insulin resistance is a matter of confusion and most of the people have both.

Insulin deficiency:

            Early in the course of type-2-diabetes, insulin secretion appears to be normal and the plasma insulin levels are not reduced. However, subtle beta cell defects in the function are found. In the normal individuals insulin secretion occurs in a pulsatile manner where as in a diabetic normal pulsatile or oscillatory pattern is lost, At about same time when the blood sugar reaches about 115 mg/dl, the rapid first phase of insulin secretion caused by chronic hyperglycemia referred to as glucose toxicity is due to reduction of GLUT-2 transporters, which facilitate glucose entry into beta cells. In due coarse of time most patients develop mild to moderate insulin deficiency. Assessment of insulin deficiency in type 2 diabetes is complicated by the occurrence of obesity.

            Even in the absence of diabetes the obesity is associated with insulin resistance and hyperinsulinemia; however when obese type 2 diabetics are compared with weight matched non diabetics, insulin levels of non diabetics, the insulin levels obese diabetics are below those observed in obese non diabetics suggesting a relative insulin deficiency. Further more in patients with moderately severe type 2 diabetes, it is possible to demonstrate an absolute deficiency of insulin.

Insulin resistance:

          In most patients with type-2-diabetes insulin deficiency is not of sufficient extent to explain the metabolic disturbances, it is logical to suspect impairment of tissues responses to insulin. Indeed there is abundant evidence that insulin resistance is major factor in the pathogenesis of diabetes. It is a complex phenomenon which is not restricted to diabetes. In both cases of obesity and pregnancy, insulin sensitivity of tissues is decreased even in the absence of diabetes. Hence the obesity and pregnancy may unmask the sub clinical type-2-diabetes by increasing the insulin resistance. Obesity an extremely important diabetogenic influence and not surprisingly over 80% of diabetics are obese. This insulin resistance can be reduced with weight loss in early stage.

Cellular basis of insulin resistance:

            Although unclear there is decrease in the number of receptors and more importantly post receptor defects including the impaired signalling.  Binding of insulin to its receptors leads to translocation of GLUT’S, particularly GLUT-4 in the muscles and fat tissues. This may account for insulin receptors in obesity and type-2-diabetes.

            We  can  conclude  that  most  patients  with  type-2-diabetes have  a  relative  or absolute deficiency. However this is milder compared to type-1-diabetes and is not an early feature of this disease. The cause for insulin deficiency in type-2-diabetes is unknown. Unlike type-1-diabetes there is no evidence of viral or auto immune mediation.

            According to one of the views, all the somatic cells of diabetics, including the pancreatic beta cells are genetically vulnerable to injury, leading to accelerated cell turnover and the premature aging and ultimately to a modest reduction in beta cells. Current interest is focused on amylin in type-2-diabetes.

            This 37 chain amino acid peptide is normally produced by beta cells, which is packaged with insulin and co-secreted in sinusoidal space.  In patients with type-2- diabetes amylin accumulates outside their cell membranes, it eventually acquires the tintorial characteristics of amyloid. Whether is the extra cellular deposits of amylin that contribute to early disturbance is yet unknown.

            In addition to insulin resistance there is increased glucose production in the liver further aggravating the hyperglycemia.

            To summarize, type-2-diabetes is a complex disease, multifactorial in origin involving both impaired insulin release and end organ insensitivity. Insulin resistance ⁴⁵ is frequently associated with obesity and produces excessive stress on beta cells which may fail in the face of sustained need for state of hyperinsulinemia. Genetic factors being more involved in Maturity Onset Diabetes in Young (MODY), but in most cases of type-2-diabetes how this fits into the puzzle remains unclear.