However, impaired first phase insulin secretion alone will not cause impaired glucose tolerance. However, deficiencies of glucokinase have not been found in other forms of type 2 diabetes 32 , In summary, the delay in the first phase of insulin secretion, although of some diagnostic import, does not appear to act independently in the pathogenesis of type 2 diabetes. Over a prolonged period of time, perhaps years, insulin secretion gradually declines, possibly as a result of intraislet accumulation of glucose intermediary metabolites Emanating from the prismatic demonstration by Yalow and Berson of the presence of hyperinsulinism in type 2 diabetes, insulin resistance has been considered to play an integral role in the pathogenesis of the disease Recent critical reviews, however, have questioned the primacy, specificity, and contribution of insulin resistance to the disease state 37 , As chronic hyperinsulinemia inhibits both insulin secretion 39 and action 40 , and hyperglycemia can impair both the insulin secretory response to glucose 41 as well as cellular insulin sensitivity 42 , 43 , the precise relation between glucose and insulin level as a surrogate measure of insulin resistance has been questioned.
Lean type 2 diabetic patients over 65 yr of age have been found to be as insulin sensitive as their age-matched nondiabetic controls Moreover, in the majority of type 2 diabetic patients who are insulin resistant, obesity is almost invariably present 45 , As obesity or an increase in intraabdominal adipose tissue is associated with insulin resistance in the absence of diabetes, it is believed by some that insulin resistance in type 2 diabetes is entirely due to the coexistence of increased adiposity Additionally, insulin resistance is found in hypertension, hyperlipidemia, and ischemic heart disease, entities commonly found in association with diabetes 16 , 48 , 49 , again raising the question as to whether insulin resistance results from different pathogenetic disease processes or is unique to the presence of type 2 diabetes 16 , 50 , Prospective studies have demonstrated the presence of either insulin deficiency or insulin resistance before the onset of type 2 diabetes Two studies have reported the presence of insulin resistance in nondiabetic relatives of diabetic patients at a time when their glucose tolerance was still normal 52 , In addition, first degree relatives of patients with type 2 diabetes have been found to have impaired insulin action upon skeletal muscle glycogen synthesis due to both decreased stimulation of tyrosine kinase activity of the insulin receptor and reduced glycogen synthase activity 54 , Other studies in this high risk group have failed to demonstrate insulin resistance, and in the same group, impaired early phase insulin release and loss of normal oscillatory pattern of insulin release have been described 56 , Based upon these divergent studies, it is still impossible to dissociate insulin resistance from insulin deficiency in the pathogenesis of type 2 diabetes.
However, both entities unequivocally contribute to the fully established disease. The ability of insulin to suppress hepatic glucose production both in the fasting state and postprandially is normal in first degree relatives of type 2 diabetic patients It is the increase in the rate of postprandial glucose production that heralds the evolution of IGT Eventually, both fasting and postprandial glucose production increase as type 2 diabetes progresses.
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Hepatic insulin resistance is characterized by a marked decrease in glucokinase activity and a catalytic increased conversion of substrates to glucose despite the presence of insulin Thus, the liver in type 2 diabetes is programmed to both overproduce and underuse glucose. The elevated free fatty acid levels found in type 2 diabetes may also play a role in increased hepatic glucose production In addition, recent evidence suggests an important role for the kidney in glucose production via gluconeogenesis, which is unrestrained in the presence of type 2 diabetes Diet therapy, although important for the prevention as well as the treatment of all stages of type 2 diabetes, continues to remain poorly understood and high controversial 59 , When obesity coexists with hyperglycemia, as seen in the majority of individuals with type 2 diabetes, weight reduction is the major goal of dietary therapy 61 — In type 2 diabetic patients, such diets may cause marked postprandial hyperglycemia.
As there is considerable patient variability in the rate of glucose absorption, arduous attention to postprandial glucose monitoring and the addition of high fiber contents to the diet become critically important. Moreover, as the glycemic response of the diet is also dependent upon the texture and content of other food stuffs in the diet as well as the rate of intestinal motility, the diet as well as the stage and duration of type 2 diabetes have to be considered on an individual basis 59 , 65 , Exercise has been shown to be beneficial in the prevention of the onset of type 2 diabetes mellitus as well as in the improvement of glucose control as a result of enhanced insulin sensitivity 67 — Decreased intraabdominal fat, an increase in insulin-sensitive glucose transporters GLUT-4 in muscle, enhanced blood flow to insulin-sensitive tissues, and reduced free fatty acid levels appear to be the mechanisms by which exercise restores insulin sensitivity In addition, exercise provides the added benefits of lowering blood pressure, improving myocardial performance, and lowering serum triglycerides while raising high density lipoprotein cholesterol levels.
In addition, several other classes of therapeutic agents will soon become available. A rational approach would be to begin with the agents particularly suited to the stage and nature of the disease, progressing, if necessary, to combination therapy. Pharmacological agents acting through different mechanisms of action should be chosen to improve glucose values while minimizing adverse effects. Sulfonylureas and related agents. As a result, calcium channels open, leading to an increase in cytoplastic calcium that stimulates insulin release A newer sulfonylurea, glimiperide, given in doses of 1, 4, or 8 mg preprandially, appears to have a more rapid onset than previous sulfonylureas both glyburide and glipizide and consequently less risk of hypoglycemia To a lesser degree than insulin administration, sulfonylureas, through endogenous hyperinsulinemia, cause a propensity for hypoglycemia and weight gain Still controversial is the influence of sulfonylureas on cardiovascular mortality, an observation first described by the University Group Diabetes Program Because of the variability of baseline data and subsequent studies that failed to substantiate the observation, sulfonylureas have not been considered to potentiate cardiovascular risk in diabetic patients However, newer data has shown that sulfonylureas, with the exception of glimiperide, block the vasodilator response to ischemia in animals, thereby potentially increasing cardiovascular risk.
At present, the question regarding sulfonylurea use in cardiac mortality in humans remains unanswered 79 , Placed in the context of our increasing understanding of the pathogenesis of type 2 diabetes, sulfonylureas would be most appropriate in those patients in whom hypoinsulinemia is the predominant cause of hyperglycemia. These patients would typically be lean, with lower basal and postprandial insulin levels.
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It is structurally different from sulfonylureas and binds to a nonsulfonylurea receptor The drug is taken preprandially and has a rapid onset and limited duration of action, which may decrease the incidence of weight gain and hypoglycemic episodes. Limited published clinical data demonstrate an efficacy similar to that of sulfonylureas; as with sulfonylureas, repaglinide shows an added benefit when given with metformin 82 , After withdrawal of the biguanide, phenformin, from the U.
Glucose lowering by the drug occurs primarily by decreasing hepatic glucose production and, to lesser extent, by decreasing peripheral insulin resistance. The drug acts by causing the translocation of glucose transporters from the microsomal fraction to the plasma membrane of hepatic and muscle cells. It does not stimulate insulin release and does not, when given alone, cause hypoglycemia Moreover, it does not cause weight gain, and it improves the lipid profile by causing a decline in total and very low density lipoprotein triglyceride, total cholesterol, and very low density cholesterol levels and an increase in high density lipoprotein cholesterol levels 85 — It is ideally suited for obese patients with type 2 diabetes who are unresponsive to diet alone and are presumed to be insulin resistant.
When introduced gradually in or mg increments to a maximum dose of mg daily, a reduction in hemoglobin A 1c HbA 1c up to 2. It is effective as monotherapy or in combination with other agents, such as insulin secretagogues, other insulin-sensitizing drugs, or inhibitors of glucose absorption. In addition, the drug should be withheld for 48 h after iv contrast administration This new class of antidiabetic agents has been under investigation since To date, the only drug brought to market is troglitazone, although companion drugs, including Pioglitazone, englitazone, and BRL are under active investigation This nuclear receptor influences the differentiation of fibroblasts into adipocytes and lowers free fatty acid levels Clinically, its major effect is to decrease peripheral insulin resistance, although at higher doses it may also decrease hepatic glucose production 15 , Although acting at a different site than metformin, both troglitazone and metformin appear to function as insulin sensitizers and require the presence of insulin for their effects 98 , In contrast to metformin, the effects of troglitazone may be progressive over time, and its full hypoglycemic potency may not be achieved until 12 weeks of therapy When given in doses of — mg daily, a maximum decrement in HbA 1c of 1.
An elevated C peptide level may help to predict a beneficial response of either drug, and as metformin and troglitazone act at different sites to restore insulin sensitivity, further improvement is seen when the two drugs are used in combination Moreover, as insulin resistance is invariably accompanied by a relative insulin deficiency, either metformin or troglitazone will be further benefited when either or both drugs are given along with an insulin secretagogue.
Troglitazone may cause peripheral edema or dilutional anemia, limiting its use in renal disease. However, the major concern of the drug is that of hepatotoxicity. Therefore, measurement of transaminases and bilirubin monthly for the first 8 months of therapy and every 2 months thereafter for the first year of therapy is mandatory. Early detection has invariably led to reversal of hepatotoxicity , Members of this class act by slowing the absorption of carbohydrates from the intestines and thereby minimize the postprandial rise in blood glucose Gastrointestinal side-effects require gradual dosage increments over weeks to months after therapy is initiated.
Serious adverse reactions are rare, and weight gain may be minimized with this therapy. Acarbose, the agent of this class in clinical use, may be added to most other available therapies Insulin therapy is indicated in the treatment of type 2 diabetes for initial therapy of severe hyperglycemia, after failure of oral agents, or during perioperative or other acute hyperglycemic states.
Insulin has been used in multiple combinations in type 2 diabetes, and new insulin analogs are in clinical trials The first available insulin analog is lispro insulin, representing a two-amino acid modification of regular human insulin. Lispro insulin does not form aggregates when injected sc, allowing it to have a more rapid onset and a shorter duration of action than regular insulin Although these properties may help minimize the postprandial rise in glucose and decrease the risk of late hypoglycemia , the use of insulin in type 2 diabetes is not without theoretical as well as practical concerns.
Insulin therapy can cause further weight gain in obese type 2 diabetics and increase the risk of hypoglycemia although less commonly than in type 1 diabetes In addition, the peripheral hyperinsulinemia achieved by exogenous insulin therapy may be a risk factor for cardiovascular disease — Most available agents have been used in combination to treat type 2 diabetes. Although many combinations are not yet approved for use, a rational choice for combination therapy would include an agent that increases insulin levels and one that enhances sensitivity to insulin and lowers glucose production.
This combination of agents would appear to correct most of the pathophysiological defects found in type 2 diabetic individuals. It is well established that an oral glucose load evokes a greater insulin response than glucose given by the iv route One of the gut polypeptides responsible for this observation is glucagon-like peptide GLP-1 Given parenterally or through the buccal mucosa, GLP-1 lowers glucose levels, decreases glucagon levels, and delays gastric emptying — Its role as an adjunctive treatment of type 2 diabetes is currently under investigation.
Caution in its application will be necessary in those patients with gastroparesis. When given parenterally, it appears to decrease the glucagon level and delay gastric emptying, thereby facilitating insulin action , It, too, will require caution in its use in patients with gastroparesis.
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Insulin-like growth factor I IGF-I levels decline with aging in parallel with the decline in insulin sensitivity Although a cause and effect relationship has not been established, the administration of IGF-I can cause a modest improvement in insulin sensitivity Its potential benefit must be balanced with the requirement for parenteral administration, expense, and theoretical potential to worsen vascular complications, particularly retinopathy Because of these concerns, IGF-I trials have been temporarily discontinued.
Any approach to treatment of type 2 diabetes must combine education, diet, exercise, and management of multiple risk factors. Control of hypertension and dyslipidemia is essential. The degree of glycemic control recommended will vary depending upon age, education, and complicating risk factors. In otherwise healthy individuals, near normalization of the glycosylated hemoglobin level is recommended , and in all cases a HbA 1c level above 8.
Whether such combinations will provide long term benefit remains to be determined.
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In just a few years in the United States, pharmacotherapy for hyperglycemia has greatly expanded, allowing many patients whose diabetes was formerly treated by insulin alone to be controlled with oral agents. However, much remains to be learned. New therapies will continue to evolve as insight into molecular mechanisms further expand our therapeutic horizon. However, we must now actively try to diagnose all type 2 diabetic individuals at an earlier stage and begin treatment in an attempt to minimize the burden of diabetes-associated complications.
Diabetologists and endocrinologists will play an essential part in this goal. Oxford University Press is a department of the University of Oxford.
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Classification of type 2 diabetes mellitus. Pathophysiology of type 2 diabetes mellitus. Insulin resistance. The liver. Therapy for type 2 diabetes mellitus. Pharmacotherapy therapy for type 2 diabetes mellitus. Combination therapies.
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Investigational therapies. Therapeutic paradigm and conclusions. Oxford Academic. Sima Publisher Humana Press Inc. Fingerprint C-Peptide.
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Coronary Artery Disease. Cardiovascular Diseases. C-Peptide: Connecting diabetes with macrovascular complications. Sima Ed. Humana Press Inc.. Porter, Karen E. Humana Press Inc. AU - Mughal, Romana S. PB - Humana Press Inc.