DIABETES MELLITUS

What is diabetes?

Diabetes mellitus is a metabolic disorder that is associated with high blood glucose levels due to either decreased production or ineffective utilization of a hormone called insulin. Diabetes is currently one of the major epidemics of our time with a rising incidence of 50% in the last 10 years. Although diabetes is prevalent throughout the world, it is more commonly seen in developed countries.

Pathogenesis

Normal Pathophysiology

The pancreas is an organ situated behind the liver and the stomach that is responsible for secreting enzymes needed for various physiological processes. Among these are insulin and glucagon, which regulate the quantity of glucose in the bloodstream. Insulin is released via the beta cells of the pancreas in response to a rise in blood sugar levels, such as seen after meals. This insulin lowers the blood glucose by increasing the entry of glucose into the cells where it is either metabolized for energy or stored for later use. Consequently, low glucose levels stimulate the release of glucagon from the pancreas which in turn stimulates hepatic glucose production.

Types of Diabetes

There are a few types of diabetes each with its characteristic pathophysiology, symptoms, and management.

Type 1 Diabetes

Type 1 diabetes is an autoimmune process that attacks and destroys the patient’s own pancreatic beta cells, responsible for producing insulin. It is a less common type making up only 10% of total diabetes cases and usually begins in childhood and adolescents. The pathophysiology of type 1 diabetes is a complicated and poorly understood process thought to be a combination of genetic and environmental factors. Due to the absence of insulin production in such patients, they must rely on insulin injections for survival.

Type 2 Diabetes

The most common type of diabetes making up 85% of the cases is type 2 diabetes. It has a multifactorial origin with both genetic and environmental risk factors that decrease the insulin sensitivity of pancreatic beta cells and adversely affect other tissues that utilize glucose such as muscles, liver, and adipose tissue. Although type 2 diabetes usually starts as decreased insulin sensitivity, with time, increased demands lead to compensatory hypersecretion of insulin by the beta cells. This ultimately leads to the inability of the pancreas to produce any insulin.

Signs and symptoms

The symptoms of diabetes can vary from patient to patient but the common general symptoms include:

Increased appetite
Extreme thirst
Unusual loss of weight
Increased frequency of urination
Decreased vision
Easy fatigability
Slowed healing
Increased risk of infections.
Mood changes

Complications

Increased levels of glucose in diabetes can lead to both immediate and long-term complications. Such complications are seen in both type 1 and type 2 diabetes. Common complications include kidney failure, heart disease, neuropathy, non-traumatic amputations, and retinopathy.

Acute metabolic complications

Acute compilations include diabetic ketoacidosis due to extremely high blood sugar and diabetic coma due to abnormally low blood sugar levels. These acute complications can be extremely severe and may lead to death.

Long-term vascular complications

These include a wide range of complications mainly due to the damaging effects of raised blood glucose on the blood vessels.

Nephropathy

Nephropathy secondary to diabetes makes up the major cause of end-stage renal disease or ESRD in the west. The patient usually presents with a long-term history of diabetes and proteinuria which is progressive and ultimately leads to decreased glomerular filtration rate and impaired kidney function. Diabetic nephropathy has a slow progression and can take up to 10-20 years to develop after the initial diagnosis.

The development and pathophysiology of diabetic nephropathy is a very complex process involving a variety of cell populations. The high levels of glucose bring about various progressive cellular effects that damage different cells of the kidney such as endothelial, smooth muscle, and mesangial cells, Other cell populations affected are the podocytes, the cells of the renal duct systems, inflammatory cells, and myofibroblasts. All these processes cause inflammation and damage to the kidney and this ultimately leads to tubulointerstitial fibrosis which is thought to be the main factor for the progression of diabetic nephropathy.

Retinopathy

Retinopathy secondary to diabetes is the major cause of blindness in adults aged 20–74 years and can be defined by a spectrum of injuries within the retina of almost all type 1 and most type 2 diabetes patients. It takes around 20 years to develop after the initial diagnosis and can be seen as adverse changes in the microvasculature of the retina. This includes altered permeability, microaneurysms, capillary degeneration, and new vessel formation. The pathophysiology also includes damage to the neural cells of the retina itself which clinically presents as an inability to distinguish colors.

In the early or non-proliferative stage of diabetic retinopathy, hyperglycemia leads to alterations in the blood vessels supplying the retina. These include changes in vascular permeability, degeneration, and occlusion of the vessels and may lead to catastrophic consequences like blindness. If not controlled, this can progress to the proliferative stage characterized by new vessel formation. These new vessels are leaky and dysfunctional ultimately causing fluid accumulation in the retina (macular edema) which clinically presents as blurred vision or blindness.

Neuropathy

Diabetic neuropathy is a condition that involves both sensory and autonomic components of the peripheral nervous systems. This complication develops in more than 50% of diabetics with some populations showing a 15% lifetime risk of lower extremity amputation due to diabetic neuropathy. Clinical presentation includes impaired spatial awareness in limbs early in the disease which means patients often can not feel injuries, especially in the lower limbs. This leads to the formation of calluses, and other foot injuries that put the patient at high risk of lower limb ulcers and amputation.

Diabetes also affects the autonomic nerves which often presents in patients as orthostatic hypotension. This is due to the inability of the nerves supplying the cranial blood vessels to properly regulate the vascular tone. Additionally, the autonomic supply to the gastrointestinal tract is also affected leading to delayed emptying of the stomach, nausea, bloating, and diarrhea.

Cardiovascular disease

Cardiovascular disease is one of the major macrovascular complications associated with diabetes mellitus and is the cause of more than 50% mortality seen in diabetic patients. This complication is characterized by atherosclerosis leading to heart attacks, and strokes. It also includes myocardial injury independent of atherosclerosis. Atherosclerosis is a multifactorial process that involves various cells and chemical processes, most probably due to endothelial injury, that leads to the formation of a fatty streak. This fatty streak, if not managed in time, can progress to complex atheromatous plaques which may then rupture and go on to cause myocardial infarction, angina, and stroke.

Other long-term complications of diabetes include depression, dementia, impaired wound healing, and sexual dysfunction which can lead to impaired quality of life in patients.

Management and Prevention

Treatment in diabetes aims to improve the quality of life and prevent the development of complications. This can be achieved by lifestyle modifications like regular exercise, weight loss, and adopting a healthy diet. Also, managing risk factors such as hypertension, and high cholesterol levels can help prevent the progression of complications.

In many cases, the use of medication or insulin injections is required to keep the blood glucose levels in check. Patient compliance, regular monitoring, and follow-ups are key to preventing complications.

References

Forbes JM, Cooper ME. Mechanisms of diabetic complications. Physiological reviews. 2013 Jan;93(1):137-88.
Plows JF, Stanley JL, Baker PN, Reynolds CM, Vickers MH. The pathophysiology of gestational diabetes mellitus. International journal of molecular sciences. 2018 Nov;19(11):3342.
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nature Reviews Endocrinology. 2018 Feb;14(2):88.
Lotfy M, Adeghate J, Kalasz H, Singh J, Adeghate E. Chronic complications of diabetes mellitus: a mini review. Current diabetes reviews. 2017 Feb 1;13(1):3-10.