Associated Disorders
Insulin resistance is associated with various other disorders, including polycystic ovary syndrome (PCOS), liver disease, and atherosclerosis.
Associated Syndromes and Etiologies
- Stress: Stress has been established as an independent risk factor for Type II diabetes. Physiologically, stress causes cortisol levels to rise, which leads to increased blood glucose, hyperinsulinemia, and, over time, truncal obesity.
- Adrenal Resistance: Increased cortisol also decreases the conversion of T4 to T3, leading to decreased metabolism, resulting in increased obesity.
- Hypothyroidism and Wilson’s Temperature Syndrome: These thyroid conditions lead to decreased metabolism that can cause obesity.
Polycystic Ovary Syndrome (PCOS)
Polycystic ovary syndrome (PCOS) is a common condition (4% to 10% of American women of reproductive age), which results in a lack of ovulation in many women. This condition can lead to amenorrhea, infertility, and hirsutism in females. It is also associated with hyperinsulinemia. PCOS can be treated as a condition of insulin resistance.
The term PCOS is used to describe a condition in which the ovaries typically contain a large number of small cysts (“polycystic”). Symptoms of PCOS may include amenorrhea (lack of menstrual period), infertility, insulin resistance, truncal obesity, and hirsutism (masculinization, such as facial hair growth). Hormone imbalances may include pituitary dysregulation, ovarian, adrenal, insulin excess (syndrome X), androgen excess, and prolactin excess.
Liver Disease
Liver disease can occur as a consequence of diabetes, and, conversely, liver disease can contribute to the development of diabetes. This is because the liver plays a central and crucial role in the regulation of carbohydrate metabolism.
A healthy functioning liver is essential for the maintenance of blood glucose levels. Insulin promotes glycogen synthesis (the storage form of glucose) in the liver and inhibits its breakdown. This allows the liver to store glucose for use when blood sugar levels fall. Insulin also promotes the liver to produce many proteins, cholesterol, and triglycerides. It inhibits hepatic release of stored glucose, stimulates glucose metabolism, and inhibits ketogenesis. The liver is the primary target organ for glucagon, which promotes the release of stored glucose when blood sugar levels fall. Insulin is also broken down in the liver and kidney.
In Type II diabetes, excessive hepatic glucose output actually contributes to the fasting hyperglycemia. Increased breakdown of stored glycogen is the predominant mechanism responsible for this increased glucose output. High levels of glucagon have been shown to augment increased rates of hepatic glucose output. In time, the abnormal glucose levels found in diabetes can result in a number of conditions of the liver, including excess glycogen deposition in the liver, steatosis (fatty liver), nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis of the liver, gallbladder disease, and gallstones.
Liver Disease Complications
Diabetes mellitus and abnormalities of glucose homeostasis occurring as a complication of liver disease:
· Hepatitis
· Cirrhosis
· Hepatocellular carcinoma
· Fulminant hepatic failure
· Post orthotopic liver transplantation
Liver disease occurring coincidentally with diabetes mellitus and abnormalities of glucose homeostasis:
· Hemochromatosis
· Glycogen storage disease
· Autoimmune biliary disease
Liver disease occurring as a consequence of diabetes mellitus:
· Glycogen deposition
· Steatohepatitis (fatty liver)
· Cirrhosis
Glycogen Deposition
Excess glycogen accumulation in the liver is seen in 80% of diabetic patients. Glycogen synthesis in the liver is impaired in diabetes due to defective activation of glycogen synthase. However, studies attesting to this have been usually performed on animals with recently induced diabetes. In patients with chronic diabetes, glycogen accumulation is seen, and it is postulated that long-standing insulin deficiency may actually facilitate synthase activity. This and enhanced gluconeogenesis may account for the net accumulation of glycogen in diabetes.
The mechanism of cytoplasmic glycogen deposition is uncertain, but is perhaps related to the large variations in glucose concentration and frequent insulin dosing. No correlation between hepatic glycogen content and fasting blood glucose levels has been demonstrated. There is also no demonstrable association between the type of diabetes or the fat content of the hepatocytes and the presence of glycogen.
The mechanism for nuclear glycogen deposition is also unclear, with the stored glycogen resembling muscle glycogen more than hepatocyte cytoplasmic glycogen. Nuclear glycogen deposition was first described by Ehrlich in 1883. It is postulated that glycogen is actually synthesized in the nucleus and has been found in 60% to 75% of diabetic patients. Nuclear glycogen deposition is also seen in sepsis, tuberculosis, some patients with hepatitis (particularly autoimmune chronic hepatitis), Wilson’s disease, and cirrhosis.
The finding of glycogen nuclei in a patient with fatty liver is useful confirmatory evidence that the fatty liver is secondary to diabetes, even if the glucose tolerance test is normal. However, other research has shown the combination in obese patients.
Patients showing solely excessive glycogen deposition may exhibit hepatomegaly and liver enzyme abnormalities, and may have abdominal pain and even nausea and vomiting but rarely ascites. All these abnormalities may improve with sustained glucose control.
Steatohepatitis (Fatty Liver)
Hepatic fat accumulation is a well-recognized complication of diabetes with a reported frequency of 40% to 70%. Unfortunately, associated obesity is a frequently occurring confounding variable. Type I diabetes is not associated with fat accumulation if glycemia is well controlled, but Type II diabetes may have a 70% correlation regardless of blood glucose control.
Fat is stored in the form of triglyceride and may be a manifestation of increased fat transport to the liver, enhanced hepatic fat synthesis, and decreased oxidation or removal of fat from the liver. The steatosis may be microvesicular or macrovesicular and may progress to fibrosis and cirrhosis. The degree of glycemic control does not correlate with the presence or absence of fat. The most common clinical presentation is hepatomegaly, and most patients have normal or only mildly abnormal transaminases and normal bilirubin.
CT scan and ultrasound are claimed to be sensitive tests for detecting hepatic fat accumulation. A negative ultrasound, however, does not exclude the presence of microscopic fatty infiltration. A liver biopsy is obviously the best method for detecting hepatic fat accumulation. It is unclear at this time whether a biopsy is always necessary in patients with suspected steatohepatitis. Biopsy probably should be performed when the diagnosis is unclear, although some authors suggest that it is necessary in all cases to confirm the diagnosis and assess the degree of fibrosis.
Excessive fat accumulation is seen in alcoholic liver disease, obesity, prolonged parenteral nutrition, protein malnutrition, jejunoileal bypass, and chronic illnesses complicated by impaired nutrition, such as ulcerative colitis and chronic pancreatitis. It can also occur as a result of hepatotoxins, such as carbon tetrachloride, and can be seen in association with abetalipoproteinemia, Weber-Christian disease, the HIV virus, cholesterol ester storage disease, and Wilson’s disease, in addition to diabetes mellitus. A number of drugs, such as amiodarone, perhexiline, glucocorticoids, estrogens, and tamoxifen, may cause macrovesicular steatosis. The amount of fat frequently diminishes with improvement of the underlying condition.
Nonalcoholic steatohepatitis (NASH) is a variant of fatty liver, in which fat in the hepatocytes is accompanied by lobular inflammation and steatonecrosis. The diagnosis can only be made in the absence of alcohol abuse or other causes of liver disease, particularly hepatitis C. In patients with diabetes and steatohepatitis, Mallory bodies, such as those evident in alcoholic liver disease, may be seen. Nonalcoholic steatohepatitis has been associated most commonly with obese women with diabetes, but the disease is certainly not limited to patients with this clinical profile. There is certainly a higher prevalence in Type II diabetic patients on insulin.
The spectrum of clinical disease in fatty liver with steatohepatitis varies from the asymptomatic elevation of liver enzymes to severe liver disease with fibrosis and nodular regeneration. Patients with nonalcoholic steatohepatitis can develop progressive liver disease and complications to the point that they may need liver transplantation.
Nonalcoholic steatohepatitis should be considered as a cause for chronically elevated liver enzymes in asymptomatic diabetic patients, particularly if they are obese and have hyperlipidemia. In Type II diabetic patients with or without obesity, up to 30% have fat with inflammation, 25% have associated fibrosis, and 1% to 8% have cirrhosis.
The morphological pattern of diabetic steatohepatitis resembles that seen in alcoholic hepatitis. However, the histopathological changes in diabetes tend to be periportal (situated in zone I), while those in alcoholic hepatitis are predominantly pericentral (in zone III). It is not clear whether the diabetes is causally related to the steatohepatitis. In an animal model of Type II diabetes, there is a high incidence of perisinusoidal hepatic fibrosis, while in humans perisinusoidal fibrosis often parallels with diabetic microangiopathy.
Gradual weight loss and good control of blood glucose levels is recommended for patients with steatohepatitis, since rapid weight loss may actually worsen NASH. Weight loss >10% has been shown to be necessary for normalization of liver enzymes in patients who are significantly overweight. Ursodeoxycholic acid may be beneficial in reducing steatosis and may result in normalization of liver enzymes and improvement in histology without demonstrable impact on fibrosis.
Cirrhosis
There is an increased incidence of cirrhosis in diabetic patients, and, conversely, at least 80% of patients with cirrhosis have glucose intolerance. The reported prevalence of cirrhosis in diabetes varies widely. Diabetes increases the risk of steatohepatitis, which can progress to cirrhosis. Obesity is a significant confounding variable in determining the prevalence of cirrhosis in diabetes. Even with normal glucose tolerance, obesity can cause steatohepatitis and cirrhosis. The lack of a clear definition of diabetes in the past somewhat confounds these statistics.
Biliary Disease, Cholelithiasis, and Cholecystitis
There is a reported increased incidence of cholelithiasis in diabetes mellitus, but obesity and hyperlipidemia may again be confounding variables. Several articles have reported a twofold to threefold increased incidence of gallstones in diabetic patients, whereas others have failed to demonstrate a significant association.
Gallbladder emptying abnormalities found in diabetic patients may predispose patients to cholelithiasis. Secretion of lithogenic bile by the liver in patients with Type II diabetes probably predisposes them to forming gallstones, but this is likely a result of concomitant obesity rather than a result of the diabetes itself. Increased biliary cholesterol saturation has not been demonstrated in insulin-dependent diabetic patients.
There is no indication in the literature that the natural history of gallstones is different in diabetic and nondiabetic individuals. The relative risk of mortality following acute cholecystitis is not significantly greater in diabetic patients than in the general population, and neither is the risk for serious complications. For that reason, prophylactic cholecystectomy cannot routinely be recommended for asymptomatic gallstones in patients with diabetes. Any increase in mortality may be attributed to underlying renal or vascular disease. Patients with diabetes have comparable survival outcomes from laparoscopic or open cholecystectomy.
The oxidation of hepatic (liver) cell membranes, which occurs in cirrhosis, causes a decrease in liver function. Since the liver is involved in blood sugar maintenance, poor liver function is associated with the development of diabetes.
