A COMPREHENSIVE DESCRIPTION OF DIABETES
Note: This information was made available from WEB MD and BRISTOL-MYERS-SQUIBB and Astra-Seneca.
Chronic hyperglycemia and physiological changes over time
The epidemic of type 2 diabetes in the United States is associated with lifestyle choices that lead to chronic hyperglycemia. The maintenance of glucose homeostasis in the body includes insulin-dependent and insulin-independent pathways of various cells and tissues. In patients with type 2 diabetes, the body’s ability to handle glucose is impaired compared with nondiabetic individuals due to dysfunction in a number of these pathways.
Glucose Absorption
The mechanisms of glucose homeostasis in the body include the actions of glucose uptake, metabolism, release, and/or storage by cells and tissues of the body. Numerous organs are involved in glucose homeostasis, including the muscle, liver, pancreas, adipose tissue, brain, and kidneys.
In nondiabetic individuals, the body regulates plasma glucose levels within a range of 70 to 110 mg/dL. This regulation is facilitated by the pancreas, which produces insulin in response to the increase in plasma glucose. Insulin promotes glucose uptake by muscle and adipose tissue, and storage by the liver. Glucose requires a transport protein to cross cell membranes. The transporter can be insulin-dependent or insulin-independent.
The liver stores glucose in the form of glycogen. Between meals, when plasma glucose concentration falls, the liver converts glycogen into glucose and releases it into the blood to keep levels from dropping too low. Under normal circumstances, the body repeats this cycle to maintain plasma glucose within the normal range.
In People with Type 2 Diabetes
Impaired insulin secretion and increased insulin resistance are core defects of the disease. Dysfunction in a number of pathways contributes to hyperglycemia, the main phenomenon of type 2 diabetes.
• Pancreas: In the beta cells, progressive impairment of insulin secretion occurs, while alpha cells contribute to excess glucagon secretion
• Liver: Insulin resistance and increased liver sensitivity to glucagon lead to excess glucose production
• Gastrointestinal (GI) tract: Decreased levels of and resistance to active incretin hormones result in defective glucose-mediated insulin secretion and increased glucagon levels
• Muscle: Insulin resistance is manifested by inefficient glucose uptake
• Adipose tissue: Increased release of free fatty acid and pro-inflammatory and proatherosclerotic adipocytokines, along with a decrease in adiponectin, induce decreased insulin sensitivity, impaired insulin secretion, and increased hepatic gluconeogenesis11,12
• Kidney: Continually filters circulating glucose and reabsorbs the glucose from the urinary filtrate back into the bloodstream13
Pathogenic Processes Leading to Type 2 Diabetes
Lifestyle choices, including overeating and lack of exercise, can lead to weight gain, followed by development of insulin resistance and increased metabolic demand for insulin.
Initially, pancreatic beta cells compensate with insulin hypersecretion. Insulin resistance, accompanied by the progressive decline in beta-cell function and relative insulin deficiency, leads to increased blood glucose levels
Once beta cells can no longer secrete sufficient insulin to compensate for insulin resistance, blood glucose rises above normal range, type 2 diabetes is diagnosed.
Lifestyle Challenges for Patients with Type 2 Diabetes
A healthy diet and exercise can reduce plasma glucose levels in patients with type 2 diabetes. Research shows that lifestyle changes, including diet and exercise, are essential to help manage glucose levels.
• A clinical trial involving 5145 Americans aged 45 to 74 years with type 2 diabetes found that after 1 year of intensive diet and exercise, 73% of patients met the ADA goal of glycated hemoglobin (HbA1c)
• A study of 251 Canadians with type 2 diabetes aged 39 to 70 years showed that patients who participated in aerobic exercise or resistance training achieved reductions in HbA1c levels by a mean of 0.51% and 0.38%, respectively, vs sedentary controls after 6 months
• A meta-analysis of 14 studies conducted in the United States and internationally involving 504 patients showed that after an average of 15-18 weeks of exercise, the mean HbA1c level for patients with type 2 diabetes was 7.65%, vs 8.31% for those who did not exercise
But most patients are not meeting their recommended diet and exercise goals.
Findings from the third National Health and Nutrition Examination Survey (NHANES III) show that:
• 62% of US adults with type 2 diabetes reported eating fewer than 5 servings of fruits and vegetables per day
• 42% reported getting 30%–40% of their daily calories from fat
• 26% indicated that >40% of their daily calories were from fat
• 61% of the respondents noted that >10% of daily calories were from saturated fats
• 31% of patients report no physical activity whatsoever
• 38% report an inadequate amount of physical activity
As many as 1 in 4 Americans are expected to have diabetes by the year 2050.
Approximately 26 million adults in the United States have diabetes, ~90% to 95% of whom have type 2 diabetes. Surveys of patients with diabetes have shown:
• About 43% are not achieving HbA1c goals
• 67% have hypertension
• 54% have hypercholesterolemia
• 55% are obese
Insights on the Renal Re-absorption of Glucose
Fasting glucose levels are controlled by the body within a range of 70-110 mg/dL. This regulation is a multi-organ process involving the pancreas, muscle, adipose tissue, liver, gastrointestinal (GI) tract, brain, and kidney.
The pancreas secretes insulin in response to increasing plasma glucose, facilitating accelerated glucose transport into cells and reducing plasma glucose levels.
TUBULES IN THE KIDNEY, WHERE GLUCOSE IS RE-ABSORBED
While insulin and insulin sensitivity are critical, plasma glucose homeostasis is a complex process involving both insulin-dependent and insulin-independent mechanisms. Research has provided a greater understanding of the role of the kidney in the insulin-independent regulation of glucose.
The Role of Insulin-Dependent Mechanisms in Glucose Homeostasis
In muscle and adipose tissue, insulin binding to insulin receptors activates transport of glucose transporter 4 (GLUT4) molecules to the cell membrane, facilitating the uptake of glucose into the cells.
In the liver, insulin regulates blood glucose levels by suppressing hepatic glucose output and increasing postprandial glucose storage in the form of glycogen.
In the GI tract, incretin hormones secreted in response to a meal promote glucose-mediated insulin secretion and suppress glucagon levels.
The Role of Insulin-Independent Mechanisms in Glucose Homeostasis
Insulin-independent mechanisms that contribute to glucose homeostasis are located mainly in the brain, liver, GI tract, and kidney.
Some sodium-glucose cotransporters (SGLTs) and some facilitative glucose transporters (GLUTs) are important insulin-independent mechanisms responsible for the transport of glucose across cell membranes of many different organs. The main known SGLTs are SGLT1, expressed mostly in the GI tract, and SGLT2, expressed mostly in the kidney.
The Role of the Kidney in Glucose Homeostasis
Among its several roles in glucose homeostasis, the kidney reabsorbs glucose. This reabsorption occurs without the assistance of insulin. Each day, the kidney filters approximately 180 g of glucose, virtually all of which is reabsorbed back into circulation.
SGLT1 and SGLT2 are expressed in the kidney, along with GLUT1 and GLUT2, where they facilitate reabsorption of filtered glucose from the renal tubules back into the blood in an insulin-independent manner.
Approximately 90% of filtered glucose is reabsorbed in the S1 segment of the proximal tubule, where SGLT2 and GLUT2 are located. The remaining 10% is reabsorbed in the S3 segment of the proximal tubule, where SGLT1 and GLUT1 are located.
Glucose will appear in the urine when plasma glucose concentrations exceed 180-200 mg/dL, or if the filtered glucose load surpasses 350 mg/min/1.73 m2.
Research has provided a greater understanding of the role of the kidney in glucose regulation in both the diabetic and nondiabetic state.
In type 2 diabetes, the kidney continues to reabsorb glucose, contributing to sustained hyperglycemia. As plasma glucose rises, so does renal glucose reabsorption. When plasma glucose concentrations reach a threshold of 180-200 mg/dL, the kidney excretes the excess filtered glucose into the urine in a process called glucuresis.
Because type 2 diabetes is the leading cause of kidney failure, the kidney is often viewed as a victim of the disease.12 But emerging understanding of renal glucose transporters helps illustrate the ways in which the kidney is an active contributor to the disease as well.
The body handles glucose through both insulin-dependent and insulin-independent mechanisms.
Dr. Pinna says:
The world pharmaceutical industry knows that diabetes is becoming a major challenge.
They are preparing doctors for new medications. It is obvious that these new medications will prevent the re-absorption of glucose from the kidney, and thereby reduce the effect of high glucose.
This medication is available and I will discuss it in my next article.
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Filed Under: Added Sugar • Diabetes • Exercise • Food • Health
