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Patho Of Type 2 Diabetes

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Genes In Type 2 Diabetes Mellitus

Diabetes Type II Pathophysiology

Physical activity has also been inversely related to body mass index and IGT. Interventional studies in China, Finland and the US demonstrated the decrease in the risk of incidence and in the progression from pre-diabetes stage to T2DM by intensive lifestyle interventions targeting diet and exercise. The Finnish Diabetes Prevention Study showed a reduction by 58% and in the china study was 31% with diet and 42% with diet and exercise. This was supported by USA study showed the same risk reduction with intensive lifestyle as in the Finnish study and also a reduction of 31% with metformin indicating that lifestyle intervention is better than drugs in T2DM prevention .

Nonetheless, non diabetes first-degree relatives of T2DM patients have an almost three fold increased lifetime risk of T2DM in comparison to the background population . In other study 40% of first-degree relatives of T2DM patients develop diabetes as compared to 6% in the general population . IR is an early metabolic feature of nondiabetic first-degree relatives of T2DM patients and also shows familial clustering in keeping with an underlying genetic predisposition . The defects of insulin action are retained in cultured skeletal muscle cells from IR subjects and T2DM patients suggesting that genetic variation contributes to decreased insulin action. While IR is a common feature of T2DM, the severity and clinical importance varies considerably across the T2DM population .

Type 2 Diabetes Blood Sugar Levels

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How Is Type 2 Diabetes Managed

Theres no cure for Type 2 diabetes. But you can manage the condition by maintaining a healthy lifestyle and taking medication if needed. Work with your healthcare provider to manage your:

  • Blood sugar: A blood glucose meter or continuous glucose monitoring can help you meet your blood sugar target. Your healthcare provider may also recommend regular A1c tests, oral medications , insulin therapy or injectable non-insulin diabetes medications.
  • Blood pressure: Lower your blood pressure by not smoking, exercising regularly and eating a healthy diet. Your healthcare provider may recommend blood pressure medication such as beta blockers or ACE inhibitors.
  • Cholesterol: Follow a meal plan low in saturated fats, trans fat, salt and sugar. Your healthcare provider may recommend statins, which are a type of drug to lower cholesterol.

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Insulin Resistance In Adipose Tissue

Resistance to the antilipolytic action of insulin

Lipolysis in adipose tissue is exquisitely insulin sensitive: in normal subjects, rates of glycerol production are half-maximally suppressed at a plasma insulin concentration just exceeding fasting concentrations. Triglyceride breakdown is increased and plasma NEFA concentrations are higher in patients with type 2 diabetes than in normal subjects studied at comparable insulin levels, suggesting that adipose tissue is also affected by insulin resistance . However, unrestrained lipolysis to a degree that could lead to ketoacidosis does not occur spontaneously in type 2 diabetes, because insulin deficiency is not sufficiently profound.

Increased NEFA concentrations may contribute to worsening of hyperglycaemia because of multiple interactions between NEFA and glucose metabolism. Increased concentration of NEFA reflects increased NEFA turnover, which increases delivery to the liver, where NEFA can be deposited as triglycerides . In the liver, NEFA also stimulate glucose production, especially via gluconeogenesis. A large increase in plasma NEFA concentrations can decrease insulin-stimulated glucose uptake and NEFA may be deposited as triglycerides in skeletal muscle .

Adiponectin deficiency

We Need A Strategy Now

[Full text] Continual evolution of type 2 diabetes: an ...

Although people with type 1 or type 2 diabetes have different journeys, including whether or not they experience symptoms, there is one issue that unites all people living with the disease. Canada has no strategy to address one of the most significant health-care crisis of our time.

With no dedicated support or action to tackle the diabetes epidemic, it means that, every 24 hours:

  • more than 20 Canadians die of diabetes-related complications
  • 480 more Canadians are diagnosed with this devastating disease
  • 14 Canadians have a lower limb amputation
  • our health care system spends $75 million treating diabetes

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What Is Type 2 Diabetes

Type 2 diabetes is a disease where your body cant use energy from food properly. Your pancreas produces insulin to help your cells use glucose . But over time your pancreas makes less insulin and the cells resist the insulin. This causes too much sugar to build up in your blood. High blood sugar levels from Type 2 diabetes can lead to serious health problems including heart disease, stroke or death.

Role Of Hepatic Circadian Clocks In Glucose Homeostasis

The liver is one of the main organs responsible for circadian control of daily glucose homeostasis . Under fasting conditions, diurnal fluctuations in the rate of hepatic glucose production dictate circadian variations in blood glycemia. Thus ablation of the SCN circadian clock abolishes circadian rhythms in blood glucose concentrations and results in disrupted glucose homeostasis . The liver also contributes to circadian control of postprandial glucose metabolism since circadian changes in the rate of hepatic glucose production are also key determinants of diurnal cycles in insulin sensitivity and meal tolerance . Moreover, key metabolic and enzymatic determinants of hepatic glucose production all have been shown to exhibit robust circadian variations in humans and a variety of animal models .

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Role Of Defects In Insulin Action And Secretion In The Natural History Of Type 2 Diabetes

There has been much debate as to whether insulin resistance is the primary defect that precedes any defect in insulin secretion in the evolution of hyperglycaemia in type 2 diabetes, or vice versa. There is a linear decrease in both first-phase insulin release and insulin sensitivity in individuals who progress from normal to impaired glucose tolerance . Once the plasma glucose concentration 2 h after an oral glucose challenge reaches the upper limit for impaired glucose tolerance ), post-glucose insulin concentrations fall and glucose then rises into the diabetic range . Similar relationships have emerged from prospective studies. Thus, low insulin sensitivity and impaired first-phase insulin release both predict type 2 diabetes . These data imply that development of overt hyperglycaemia requires a relative decrease in insulin secretion as depicted in Fig.

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A Central Nervous System Channelopathy In Diabetes

Type 2 Diabetes Pathophysiology (Step-By-Step)

FIGURE 19.13. voltage-gated sodium channel gene expression in hypothalamic magnocelluar neurons is upregulated in diabetes. A:In situ hybridization shows upregulated sodium channel Nav1.2 and Nav1.6 mRNA levels in the SON after 6 weeks of STZ-induced diabetes. B: Immunocytochemistry using subtype-specific antibodies shows upregulated Nav1.2 and Nav1.6 protein after 6 weeks of STZ-induced diabetes, demonstrating that the newly produced mRNA is translated into sodium channel protein. C: Quantification of optical intensities of individual SON neurons shows increases in Nav1.2 and Nav1.6 mRNA and protein. mRNA and protein data shown in A and B are represented in the histogram in C black bars = control, white bars = diabetic, data plotted as mean ± SE, * = & lt .05 by non-paired t-test. Modified from Klein et al. .

FIGURE 19.14. Patch clamp recordings of acutely dissociated MNCs from diabetic rats show increased peak and ramp currents and current densities , indicating that increased numbers of functional sodium channels have been inserted within the membranes of diabetic MNCs black bars = control, white bars = diabetic, data plotted as mean ± SE, * = P& lt .05 by non-paired t-test. Reproduced from Klein et al. .

Marie-Eve Piché, Paul Poirier, in, 2018

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Pathophysiology Of Type 2 Pathophysiology Of Type 2 Diabetes Diabetes

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Itching And Yeast Infections

Excess sugar in the blood and urine provides food for yeast, which can lead to infection. Yeast infections tend to occur on warm, moist areas of the skin, such as the mouth, genital areas, and armpits.

The affected areas are usually itchy, but a person may also experience burning, redness, and soreness.

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Increase Hepatic Glucose Production

In type II diabetes mellitus, insulin resistance in the liver reflects the failure of hyperinsulinemia to suppress gluconeogenesis. This results in fasting hyperglycemia and decreased glycogen storage by the liver in the post-prandial state. Increased hepatic glucose production occurs early in the disease course of diabetes, likely after the onset of insulin secretory abnormalities and insulin resistance in the skeletal muscle.

Hepatic glucose production is regulated by two rate-limiting enzymes namely, glucose 6-phosphatase catalytic subunit, encoded byG6PC and phosphoenolpyruvatecarboxykinase, encoded by PCK1 and PCK2. As the expression of these enzymes is suppressed by insulin, it has been widely held that patients with type II diabetes would have increased expression of G6PC and PCK, due to hepatic insulin resistance.

Early Signs And Symptoms Of Type 2 Diabetes

Pathophysiology of type 2 diabetes mellitus (T2DM ...

Type 2 diabetes is a disease in which your body doesnât make enough of a hormone called insulin or doesnât use insulin the way it should. Insulin helps carry glucose to your cells. So when thereâs a problem with the insulin, glucose builds up in your blood. Youâve probably heard this called high blood sugar.

About 90% of people who have diabetes have type 2. The other two main ones are type 1, in which your body stops making insulin, and gestational, which happens in pregnant women.

You can usually control type 2 diabetes with lifestyle changes. Some people also need medication.

You might not know that you have type 2 diabetes until it affects your health. About 1 in 4 people with the condition donât know that they have it.

Symptoms can come on slowly. They may include:

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Is Type 1 Diabetes An Autoimmune Disease

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Classification Of Type 2 Diabetes Mellitus

The definition of type 2 diabetes mellitus, previously termed noninsulin-dependent diabetes mellitus, was recently modified by the American Diabetes Association. Several criteria may be used independently to establish the diagnosis: 1) a 75-g oral glucose tolerance test with a 2-h value of 200 mg/dL or more, 2) a random plasma glucose of 200 mg/dL or more with typical symptoms of diabetes, or 3) a fasting plasma glucose of 126 mg/dL or more on more than one occasion . Fasting glucose values are preferred for their convenience, reproducibility, and correlation with increased risk of microvascular complications.

The term impaired fasting glucose has been defined as fasting plasma glucose of 110 or more and 125 mg/dL or less . Impaired glucose tolerance is defined as a 2-h plasma glucose value of 140 or more and of less than 200 mg/dL during an oral glucose tolerance .

Individuals with impaired fasting glucose and IGT are considered to be at high risk for the development of diabetes and macrovascular disease . Although one third of these patients will eventually develop diabetes, dietary modification and exercise can lower the risk of progression from impaired glucose tolerance to type 2 diabetes and may also prevent the development of IGT in nondiabetic individuals at high risk . Pharmacological agents may also be of benefit in limiting the progression from IGT to diabetes .

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Importance Of Early Diagnosis

An early diagnosis may help prevent complications.

Recognizing the early signs of type 2 diabetes can allow a person to get a diagnosis and treatment sooner. Getting appropriate treatment, making lifestyle changes, and controlling blood sugar levels can greatly improve a persons health and quality of life and reduce the risk of complications.

Without treatment, persistently high blood sugar levels can lead to severe and sometimes life-threatening complications, including:

The Past: Identification Of

Type 2 Diabetes: Pathophysiology

Development of the insulin radioimmunoassay led to the identification that individuals with early maturity onset diabetes produced insulin and secreted this hormone in response to nutrient ingestion. Subsequently, it was shown that these individuals manifest a defect in the ability of the islet -cell to respond to intravenous secretagogues including glucose.

In these earlier days it was demonstrated that these individuals also did not respond well to insulin and were thus deemed to be insulin-insensitive. It was subsequently shown that this contributed to increased glucose production by the liver and decreased glucose uptake in muscle and adipose tissue. Today we recognize that a proportion of these abnormalities are explained by adiposity, especially that located within the intra-abdominal cavity.

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Insulin Secretion Function And Impairment

Insulin is synthesized and produced by – cells in the pancreas. It is a peptide hormone regulates the metabolism of fat and carbohydrate in the body. It helps glucose absorption from the circulation by fat tissue and skeletal muscles. Figures 1 and 2 .

Figure 1.

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Insulin is secreted from the secretory cells by priming reaction. Each cell contains thousands of secretory vesicles/granules. Less than < 5% of these cells exist to release the readily pool insulin by exocytosis followed by minimal latency of immediate releasable pool of insulin. The bulk of granules in the cell exist in a non-releasable reserve pool of insulin, which must undergo a series of ATP-, Ca2+-, and temperature-dependent reactions to release insulin .

The prevalence of Gestational diabetes is 2-3% of all pregnant women. GDM women have the same second phase insulin response as women with normal oral GTT. But, the first phase-insulin secretion is reduced with intravenous glucose and has a later peak rise with OGTT. Both groups showed a decreased in IS by 50-70%, this is back to normal in postpartum period in women with normal OGTT but this is not in women with GDM. In the same period, the latter group also demonstrated a persistent and excessive proinsulin secretion. Women with GDM have also a substantial increase in insulin secretion with OGTT or a meal compared to the same women in postpartum period. But this rise is less in women with GDM compared with pregnant women who retain normal OGTT .

Circadian Organization Molecular Structure And Entrainment

The majority of organisms have evolved optimal physiological functionality under environmental conditions created by daily changes in the light-dark cycle. The driving force behind biological adaptation to changes in LD cycle is precipitated by the evolutionary development of the circadian system. The primary utility of the circadian system is to promote adaptation and organismal fitness in response to 24-h environmental cycles . A key aspect of circadian physiology is its intrinsic nature, suggesting the presence of an internal cell-specific temporal program that anticipates and regulates behavioral, physiological, genetic, and metabolic cycles appropriate for the outside environment . Thus evolutionary origins of the circadian system appear to be selected to promote organismal adaptation to diurnal changes in oxidative environment, UV-mediated DNA damage, as well as optimal diurnal regulation of cellular energetics and metabolism . Indeed, a functional circadian system has been shown to provide a clear fitness advantage to organisms from diverse living phyla such as plants , bacteria , yeast , and mammals .

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Systemic And Islet Cell Inflammation

Figure 2 from Global aetiology and epidemiology of type 2 ...

Obesity is frequently characterized by systemic inflammation. Cumulatively, both of these contribute to beta cell dysfunction. Research data show that systemic inflammatory markers such as C-reactive protein and its up-regulator, interleukin-6 are directly related to insulin sensitivity and beta cell function. Increased adiposity is associated with increased expression of pro-inflammatory genes, which may impair insulin signaling. Other pro-inflammatory markers such as cytokines,are released into the circulation where they can act at distant sites such as liver and skeletal muscle to worsen insulin resistance.

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