Consequence Of Insulin Resistance Research Articles

Understanding the pathogenesis of type 2 diabetes: can we get off the metabolic merry‐go‐rounds?

The aetiology of non-insulin-dependent diabetes mellitus (NIDDM) is not known. The concordance of NIDDM in identical twins and differences in the prevalence rate of NIDDM between different racial groups suggest a genetic cause. Hyperglycaemia in established diabetes is caused by a combination of hepatic insulin resistance, impaired peripheral (muscle and fat) glucose uptake and a defect in glucose-mediated insulin secretion. However, it is not known if these defects are all inherited or if one can cause the others. This uncertainty is due to the fact that hyperglycaemia per se can cause defects in insulin action and insulin secretion that resemble those found in NIDDM. Furthermore the elevated free fatty acid (FFA) levels found when NIDDM is associated with obesity are known to cause both peripheral and hepatic insulin resistance. Recently we have demonstrated the mechanism by which elevated FFA levels can cause hepatic insulin resistance. However, we also have evidence that the converse holds in that genetically engineered hepatic insulin resistance in a transgenic rat model leads to obesity. Thus an understanding of the pathogenesis of NIDDM is complicated by the fact that hyperglycaemia and obesity can be both causes and consequences of insulin resistance. To overcome these difficulties, studies in young euglycaemic diabetes-prone subjects have been conducted. Results suggest that there may be different causes for NIDDM in different racial groups.

Insulin-induced decline of plasma amino acid concentrations in obese subjects with and without non-insulin-dependent diabetes

Obesity-associated hyperaminoacidemia is traditionally interpreted as a consequence of insulin resistance. We performed two different experiments to investigate the effects of both obesity-associated insulin resistance and the insulin resistance of non-insulin-dependent diabetes mellitus (NIDDM) on amino acid metabolism. In the first experiment, we measured postabsorptive amino acid concentrations and their decline in response to an oral carbohydrate load in 19 obese nondiabetic women and 19 normal-weight nondiabetic controls. Obese subjects were more resistant to insulin with respect to its effects on glucose metabolism than normal-weight controls, as calculated by the method described by Matthews. However, postabsorptive plasma concentrations of the so-called large neutral amino acids (LNAA), namely phenylalanine, tyrosine, valine, leucine, and isoleucine, and their decrease in response to carbohydrate consumption were similar in both groups. In the second experiment, we compared the decrease of plasma concentrations of LNAA during a euglycemic, hyperinsulinemic clamp in obese subjects with and without NIDDM. Peripheral glucose uptake (PGU) was more impaired in NIDDM subjects compared with obese controls. Furthermore, hepatic glucose production (HGP) was less attenuated by insulin infusion in NIDDM than in control subjects. Postabsorptive plasma LNAA concentrations were not different in the two groups. Values obtained in either group were not different from the postabsorptive concentrations in the normal-weight control subjects of experiment 1. All amino acid levels decreased substantially in response to insulin infusion. The magnitude of the decrease was not significantly different in the two groups, except for a slightly greater decrease of the plasma isoleucine concentration in obese control subjects. These results indicate that insulin resistance in obesity and NIDDM has dissociated effects on insulin-mediated glucose and amino acid metabolism. Although obese subjects both with and without NIDDM were resistant to insulin with respect to its effects on glucose metabolism, postabsorptive plasma levels of LNAA and their decrease in response to carbohydrate consumption or insulin infusion were similar in obese subjects, irrespective of the presence of NIDDM, and normal-weight control subjects.

Reduced Glucose-Induced Thermogenesis Is Present in Noninsulin-Dependent Diabetes Mellitus without Obesity*

Decreased glucose-induced thermogenesis has been observed in all forms of obesity. However, some studies implicate insulin resistance rather than obesity per se as the mechanism by which glucose-induced thermogenesis is reduced. To establish the role of insulin resistance in reduced thermogenesis independent of obesity, we compared energy expenditure in 9 nonobese individuals with noninsulin-dependent diabetes mellitus (NIDDM) to 16 nonobese control subjects using indirect calorimetry and the hyperinsulinemic clamp technique. To document the presence of insulin resistance and reduced glucose-induced thermogenesis in nonobese NIDDM, 6 individuals from each group were studied under identical conditions of hyperinsulinemia (120 mU/m2.min) and euglycemia (approximately 5 mmol/l). Both glucose uptake (0.482 +/- 0.042 vs. 0.737 +/- 0.040 g/min) and energy expenditure above basal (0.04 +/- 0.02 vs. 0.10 +/- 0.02 kcal/min) were decreased in nonobese NIDDM compared to control subjects (both P less than 0.05). To determine whether decreased glucose-induced thermogenesis could be overcome by correcting for reduced glucose uptake, the 9 nonobese NIDDM individuals were age and weight-matched to 9 control subjects and clamps were performed at matched rates of glucose uptake. During a 40 mU/m2.min insulin infusion, the nonobese NIDDM individuals were studied at hyperglycemia (17.5 +/- 1.9 mmol/L) and compared to the control subjects at euglycemia (5.1 +/- 0.1 mmol/L; P less than 0.05). Under these conditions, both groups achieved similar rates of glucose uptake (0.698 +/- 0.040 vs. 0.688 +/- 0.038 g/min, NIDDM and control subjects, respectively) and similar rates of energy expenditure above basal (0.08 +/- 0.03 vs. 0.06 +/- 0.02 kcal/min, P = NS). During 600 mU/m2.min clamps performed at hyperglycemia (19.0 +/- 1.2 vs. 14.5 +/- 1.1 mmol/L, NIDDM vs. control subjects, respectively; P less than 0.05), rates of maximal glucose uptake (1.538 +/- 0.093 vs. 1.518 +/- 0.047 g/min) and energy expenditure above basal (0.34 +/- 0.03 vs. 0.31 +/- 0.03 kcal/min) were also similar (P = NS). In conclusion nonobese NIDDM is associated with both decreased rates of glucose uptake and decreased glucose-induced thermogenesis. Decreased glucose substrate availability, due to impaired insulin action, appears to be the critical determinant of glucose-induced thermogenesis in nonobese NIDDM. These data indicate that decreased thermogenesis in NIDDM is a consequence of insulin resistance and can occur independent of obesity.

Contribution of Impaired Muscle Glucose Clearance to Reduced Postabsorptive Systemic Glucose Clearance in NIDDM

The reduced postabsorptive rates of systemic glucose clearance in non-insulin-dependent diabetes mellitus (NIDDM) are thought to be the consequence of insulin resistance in peripheral tissues. Although the peripheral tissues involved have not been identified, it is generally assumed to be primarily muscle, the major site of insulin-mediated glucose disposal. To test this hypothesis, we measured postabsorptive systemic and forearm glucose utilization and clearance in 15 volunteers with NIDDM and 15 age- and weight-matched nondiabetic volunteers. Although systemic glucose utilization was increased in NIDDM subjects (14.5 +/- 0.5 vs. 11.2 +/- 0.2 mumol.kg-1.min-1, P less than 0.001), systemic glucose clearance was reduced 1.40 +/- 0.06 vs. 2.13 +/- 0.05 ml.kg-1.min-1, P less than 0.01). Although forearm glucose utilization was increased in NIDDM subjects (0.663 +/- 0.058 vs. 0.411 +/- 0.019 mumol.dl-1.min-1, P less than 0.001), forearm glucose dl-1 clearance was reduced (0.628 +/- 0.044 vs. 0.774 +/- 0.037 ml.L-1.min-1, P less than 0.01). However, extrapolation of forearm data to total-body muscle indicated that impaired clearance reduced muscle glucose disposal by only 61 +/- 21 mumol/min, whereas impaired systemic clearance reduced systemic glucose disposal by 662 +/- 82 mumol/min. Thus, impaired muscle glucose clearance accounted for less than 10% of the reduced systemic glucose clearance in NIDDM subjects. Therefore, we conclude that muscle insulin resistance plays only a minor role in the reduced systemic glucose clearance found in NIDDM in the postabsorptive state and propose that reduced brain glucose clearance is largely responsible.

Classification and Diagnostic Criteria for Diabetes Mellitus and Other Categories of Glucose Intolerance

Diabetes mellitus is composed of a heterogeneous group of disorders characterized by high blood glucose levels. Four major types of diabetes have been defined by the National Diabetes Data Group. Insulin-dependent diabetes (IDDM), also called type I diabetes, is characterized by abrupt clinical onset, insulinopenia, proneness to ketosis even in the basal state, and dependence on exogenous insulin to sustain life. Non-insulin-dependent diabetes (NIDDM), also called type II diabetes, may remain relatively asymptomatic for years. Insulin levels may be normal, lower than normal, or elevated as a consequence of insulin resistance. Ketosis is not part of the general clinical picture except in times of metabolic stress, although the classic complications of diabetes can be expected to develop in long-duration diabetics. Gestational diabetes (GDM) refers to the recognition of abnormal glucose intolerance in pregnancy, although unrecognized abnormal tolerance may indeed have predated the pregnancy. Rates of macrosomia are higher than in non-GDM pregnancies, but fetal mortality and congenital anomalies appear to be no greater than in the general population. Other types of diabetes include a number of diverse conditions in which glucose intolerance is a feature and in which it may be etiologically related. Impaired glucose tolerance (IGT) is a class that encompasses persons whose glucose tolerance is intermediate between normal and diabetic. These individuals do not manifest the microvascular complications of diabetes, but they appear to have higher rates of macrovascular disease associated with the known cardiovascular risk factors. Two statistical risk categories have also been defined that replace the older terms prediabetes, potential diabetes, and latent diabetes. Diabetes can be diagnosed by the presence of classical signs and symptoms of diabetes and unequivocally elevated blood glucose levels; by a fasting plasma glucose greater than or equal to 140 mg/dl; or by an abnormal oral glucose tolerance test, with a venous plasma glucose value greater than or equal to 200 mg/dl at 2 hours after 75 grams oral glucose, being a hallmark criterion for diabetes. For the latter two criteria, the abnormality should be reconfirmed at a later occasion before a definitive diagnosis of diabetes is made. The oral glucose tolerance test has been standardized at a 75-gram glucose (or carbohydrate equivalent) load, given in the morning after an overnight fast. Glucose should be determined for two hours after administration of the challenge.

Abnormalities of pancreatic exocrine function in obesity: Studies in the obese mouse

1. 1. Insulin is known to play a specific role in the biosynthesis of pancreatic amylase. 2. 2. In the insulin resistant adult C57 BL/6J— ob/ob mouse there is a reduction of pancreatic amylase content. The differences of enzyme content could not be explained by differences of food intake between obese and lean mice, but are more likely to be the consequence of insulin resistance at the level of the exocrine pancreas. 3. 3. By contrast, greater pancreatic content of amylase and lipase seen in young obese mice (less than 2-months old) was associated with the greater food intake of these mice with respect to lean controls.

Plasma amino acid response to protein ingestion in patients with liver cirrhosis

The metabolic effects of a protein-rich meal were studied for 3 h in 10 controls and in 20 cirrhotic patients. After protein ingestion, blood glucose did not vary significantly. Insulin and glucagon levels rose in controls and, more markedly, in cirrhotics. Aromatic amino acids and tryptophan increased more in cirrhotics as a result of their decreased liver function. Similarly, branched-chain amino acids increased by 153 ± 14 nmol/ml · min (mean ± SE) in controls and by 259 ± 27 nmol/ml · min in cirrhotics (p < 0.02), in the presence of a markedly increased insulin response. Branched-chain amino acid metabolism mainly occurs in skeletal muscle under insulin control; in cirrhosis, it might be reduced as a consequence of insulin resistance. To support this hypothesis, the effects of the protein meal were compared with those of an oral glucose load in 15 cirrhotic patients. Branched-chain amino acid response to protein ingestion significantly correlated with blood glucose response to oral glucose (r = 0.714), and with insulin resistance during the glucose tolerance test, when assessed by the insulinogenic index (r = 0.628). Similarly, in 8 patients, increased branched-chain amino acid response also correlated with the index of tissue sensitivity to insulin obtained by means of the glucose clamp technique during continuous insulin infusion (r = −0.809). We conclude that liver cirrhosis is characterized by an abnormal branched-chain amino acid response to protein ingestion, which matches the well-known intolerance to oral glucose. Both alterations are possibly due to decreased peripheral insulin activity on substrates.

Non Alcoholic Fatty Liver Disease- Is It Always Benign?

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease observed in the clinical practice of hepatology affecting approximately 20% of the general population. It is increasingly apparent that non alcoholic steatohepatits (NASH) and NAFLD are not Western disease. There is evolution of Western-style life among the Asian population and NASH has increasingly been diagnosed in several regions in Asia. NASH is considered as a type of a larger spectrum of NAFLD that is a consequence of insulin resistance and other underlying factors with histological findings ranging from fatty change alone to fat plus inflammation, to fat plus ballooning degeneration, and to fat plus alcoholic hepatitis-like lesions including Mallory body and fibrosis, the latter two categories being considered as NASH. Although liver biopsy is currently the gold standard for diagnosis, there is a need for less invasive methods. Imaging by ultrasound, computerized tomography and magnetic resonance are all able to demonstrate fat. Ultrasound, although probably not the most reliable imaging method, has many advantages and, when positive, gives a high degree of certainty of the diagnosis depending on the prevalence of fatty liver in the population being studied. Unlike liver biopsy, none of these techniques is able to differentiate simple steatosis from non- alcoholic steatohepatitis. The ultimate goal of treating the patient with NASH is to prolong life by avoiding the end-organ diseases associated with insulin resistance and the metabolic syndrome. Treatment of patients with nonalcoholic fatty liver has typically been focused on the management of associated conditions as well as discontinuation of potentially hepatotoxic drugs. Weight loss and exercise improve insulin sensitivity. Bariatric surgery may improve liver histology in patients with morbid obesity. Insulin sensitising drugs showed promise in pilot trials as have a number of hepatoprotective agents. Further randomised, well controlled trials are required to determine the efficacy of these drugs. &#x0D; &#x0D; In this article, we will review (1) various processes that are involved in the pathogenesis of NASH (2) the existing medical therapy for patients with nonalcoholic fatty liver, (2) the emerging and potentially useful medications. &#x0D; &#x0D; (J Bangladesh Coll Phys Surg 2007; 25 : 144-152)