The Concept of Early Insulin Therapy in type 2 DM
Dr. P. Ramakrishnan MD(Med), Cochin Hospital

Diabetes is a group of metabolic disease characterized by hyperglycemia resulting from defect in insulin secretion, insulin action or both. Impairment of insulin secretion and defects in insulin action frequently coexists in the same patient and it is often unclear which abnormality is the primary cause of the hyperglycemia. It is widely accepted that insulin resistance is an early finding, evident before the onset of hyperglycemia and predictive of the development of diabetes. However, recent studies clearly indicate that early phase insulin secretary defect may be the initial abnormality in the development of type 2 diabetes. Further insulin secretory dysfunction in type 2 diabetes is both quantitative and qualitative. In addition to the relative impairment in the amount of insulin released, the pattern of insulin secretion is abnormal. The role of Early Insulin Secretion The early first phase of insulin secretion is an important physiological response to rapidly shift the metabolic process from the fasting to the parandial (fed) state. The initial increase in plasma glucose upon the ingestion of a meal stimulates rapid increase in insulin secretion. The antilipolytic action of insulin causes rapid decrease in non-esterified fatty acids and inhibition of endogenous glucose production. The early insulin secretion also primes the insulin sensitive tissues to increase the efficiency of glucose disposal. Thus within minutes, the metabolic state is efficiently shifted from glucose production towards glucose disposal. Loss of first phase insulin secretion may alter the signaling capacity of hormones. It may be one of the factors implicated in the genesis of insulin resistance. In the absence of first phase insulin secretion, the stimulatory effect of glucagons on gluconeogenesis is enhanced. Marked impairment in the first phase insulin secretory response occurs to intravenous glucose at a very early stage in the development of hyperglycemia. This becomes evident as by the time fasting plasma glucose concentration exceeded 109 mgs/dl (6.1 mmol/L), the first phase insulin response was found to be mostly absent. In non-diabetic subject, endogenous glucose production was promptly suppressed by more than 50% within thirty minutes of the meal. In contrast, in patients with diabetes, endogenous glucose production was approximately 50% higher at baseline and was not suppressed until 2 hours after the ingestion of a meal. Thus the inadequate suppression of endogenous glucose production resulting from impaired or absent early phase insulin secretion results in postprandial hyperglycemia. Loss of early insulin secretion is apparently the critical event in the development of glucose intolerance. The early rise in plasma insulin concentration ensures a smoother prandial glucose profile;
it may relieve the stress on the beta cell and reduce the prevalent hyperinsulinemia of the late phase after the ingestion of a meal. The strategy is to look for the potential therapeutic agents that augment early insulin secretion. Rationale for Insulin Administration as First Line Therapy It has already been alluded to that the acute insulin response is lost if the fasting plasma glucose level exceeds 109 mg/dl and is associated with a progressively greater risk of developing micro and macrovascular complications. The physiological therapeutic approach should be to restore the defective early phase insulin secretion by insulin and not by drugs to stimulate insulin secretion that are likely to cause beta cells apoptosis in the future. The current treatment of type 2 diabetes extensively uses sulfonylurea compounds that stimulate insulin secretion through glucose like effect on the K+-ATP channel. It seems possible that long term treatment with sulfonylurea could over stimulate Beta cells, resulting negative consequences. The frequency of hypoglycemic episodes, weight gain and loss of clinical efficacy in the long term are some of the drawbacks with them. Yet another undesirable action of sulfonylurea is their ability to stimulate amyloid formation. Amylin and insulin are co-located in the beta cells. Any stimulus that induces the secretion of insulin also stimulates the co-secretion of Amylin. Amylin (Islet Amyloid Peptide) is a constituent peptide of amyloid deposits. The amyloid deposits form between islet cells and capillaries. Accumulations of these deposits destroy islet endocrine cells and results in progressive worsening of beta cell function. Therapy with sulfonylureas by increasing the concentration of constituent peptides of islet amyloid may lead to a greater deposition of islet amyloid and faster decline in beta cell function in type 2 diabetes than therapy with diet or insulin. If one is compelled to use oral agent, probably the safe choice should be insulin sparing sulfonylureas (glimipride) or non-sulfonylureas secretagogues (repaglinide or netaglinide).
In the natural history of diabetes, the blood glucose levels at which the insulin secretion declines could be an indicator of early insulin intervention. Very few persons with a fasting plasma glucose concentration above 109mg/dl, the lower cut off for the recently defined category of impaired fasting glucose are able to mount even a minimal response to IV glucose challenge. With fasting plasma glucose of more than 140 mg., 75% of beta cell function is lost and the acute insulin response is totally lost with the fasting plasma glucose above 180 mgs./dl. Similarly, insulin secretion starts to become impaired with 2-hour plasma glucose value during OGTT exceeding 200 mg/dl. If the beta cell secretion is declining, the attempt should be to replace insulin which is deficient, instead of stimulating the beta cell secretion;
the attempt should be to replace insulin which is deficient, instead of stimulating the beta cell which is bound to fail over time. A reduced need for insulin production will reduce the production of amyloid peptide. This is achieved by early insulin therapy in the course of type 2 diabetes. One should consider insulin when fasting plasma glucose is more than 140 mg, as at this level more than 75% of beta cells are lost. Controlling plasma glucose not mean correcting the underlying pathogenesis, which has caused hyperglycemia. Treating by any other means, other than insulin amounts to whipping the surviving 25% of beta cells to compensate for the loss of 75% of beta cell function. This approach is unphysiological as the aim is to preserve the beta cell function. Inducing better control by intensive insulin treatment in type 2 diabetic patents has repeatedly been shown to improve insulin secretion. Cerasi et al* induced long-term glycemic control in newly diagnosed
type 2 diabetics by a short term intensive insulin treatment. According to standard practice when diet fails oral agents and/or insulin are added. In their study, they observed that normalization of blood glucose using transient intensive insulin treatment, re-established diet responsiveness for several years. The amount of total daily insulin needed was 0.6 units/kg, which was less than the endogenous insulin production in non-diabetics. Hence, the concern of treatment-induced hyperinsulinemia is unwarranted. Further, the transient nature of the treatment should alleviate such fears. A similar observation was made by Sahay et al. (personal communication) from Hyderabad. These findings suggest that the present approach of using oral hypoglycemic agents in the management of newly diagnosed type 2 diabetes may need revision. The metabolic disturbance I the natural history of type 2 diabetes does not occur in sequential events. The insulin secretory dysfunction and resistance to the action of insulin occurs in every stage of the disease as it progresses from normal glucose tolerance to frank diabetes and thus both these abnormalities are to be addressed in the prevention and management. A logical approach to correct the pathogenesis of hyperglycemia is to restore insulin deficiency and to rectify resistance t the action of insulin. This is possible in persons who fail to respond to a meal plan with oral anti diabetic drugs or insulin, but the later mode of therapy has a distinct advantage. With the normalization of blood sugar, by using insulin, the glucotoxicity declines and the insulin secretion and action improves. After the correction of glucotoxicity, further management could be insulin or insulin sparing secretogogues with or without combination of insulin sensitizers. Probably by practicing evidence-based medicine to protect and preserve the beta cells, the life of diabetics will be a lot more better in the future.