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• Autosomal dominant hypoparathyroidism results from gain-of-function mutations in the calcium-sensing receptor (CASR) gene
• Heightened calcium sensing from inappropriate CASR activity suppresses PTH, leading to hypocalcemia and hypercalciuria
• Loss-of-function CASR mutations are a rare cause of familial parathyroid adenomas
• Familial isolated hypoparathyroidism (FIH) is a rare condition with autosomal dominant or recessive inheritance
• Autosomal dominant FIH happens due to a mutation in the PTH-encoding gene, which impairs PTH processing
• Autosomal recessive FIH happens due to loss-of-function mutations in the GCM2 transcription factor gene, essential for parathyroid development
• Congenital absence of parathyroid glands can occur with other malformations like thymic aplasia and cardiovascular defects, or as part of the 22q11 deletion syndrome (DiGeorge syndrome)

Clinical Features

• Hypoparathyroidism's major manifestations are related to hypocalcemia's severity and chronicity
• Tetany is the hallmark of hypocalcemia, marked by neuromuscular irritability from decreased serum calcium levels
• Symptoms range from circumoral numbness or paresthesias and carpopedal spasm, to life-threatening laryngospasm and generalized seizures
• Chvostek and Trousseau signs are classic physical exam findings
• Chvostek sign: tapping along the facial nerve course induces contractions of eye, mouth, or nose muscles
• Trousseau sign: carpal spasms result from occluding circulation to the distal arm using a blood pressure cuff for a few minutes
• Mental status changes: emotional instability, anxiety, depression, confusional states, hallucinations, and frank psychosis
• Intracranial manifestations: calcifications of the basal ganglia, parkinsonian-like movement disorders, and increased intracranial pressure with papilledema
• Hypocalcemia can paradoxically associate with calcifications because of increased phosphate levels that lead to calcium phosphate deposition
• Ocular disease may involve lens calcification, resulting in cataract formation
• Conduction defects prolonging the QT interval in the electrocardiogram are cardiovascular manifestations
• Dental abnormalities result if hypocalcemia occurs during early development and may include: dental hypoplasia, failure of eruption, defective enamel and root formation, and abraded carious teeth

Pseudohypoparathyroidism

• Hypoparathyroidism happens because of end-organ resistance to PTH actions, but PTH levels happen to be normal or elevated
• There is end-organ resistance to TSH and FSH/LH along with PTH
• Hormones signal through G-protein-coupled receptors, and genetic defects in pathway components shared across endocrine tissues cause this disorder
• PTH resistance represents the most obvious clinical manifestation with hypocalcemia, hyperphosphatemia, and elevated circulating PTH
• TSH resistance is generally mild, while LH/FSH resistance manifests as hypergonadotropic hypogonadism in females

The Endocrine Pancreas

• The endocrine pancreas is made up of approximately 1 million cell clusters, called the islets of Langerhans, which contain four major and two minor cell types
• The four main types are β, α, δ, and PP (pancreatic polypeptide) cells, and their granules and hormone content differentiate them under a microscope
• The Β cells produce insulin, which regulates glucose utilization in tissues to reduce blood glucose levels
• The α cells secrete glucagon, which increases blood sugar by stimulating glycogenolysis in the liver
• The δ cells secrete somatostatin, which suppresses insulin and glucagon release
• The PP cells secrete pancreatic polypeptide stimulating gastric and intestinal enzyme secretion, plus inhibiting intestinal motility and can be found in the islets as well as being scattered throughout the exocrine pancreas
• Two rare types: D1 cells and enterochromaffin cells, where D1 elaborate vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and hyperglycemia and also stimulates gastrointestinal fluid secretion to induce secretory diarrhea
• Enterochromaffin cells synthesize serotonin and source tumors that cause carcinoid syndrome
• The 2 main islet cell disorders are diabetes mellitus and pancreatic endocrine tumors

DIABETES MELLITUS

• Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both
• Chronic hyperglycemia and metabolic deregulation can cause secondary damage in multiple organ systems like the kidneys, eyes, nerves, and blood vessels
• Diabetes is the leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower extremity amputations in the United States
• According to the American Diabetes Association, diabetes affects over 30 million children and adults, or over 9% of the United States population, Approximately 1.2 million have type 1 diabetes and remaining have type 2
• Approximately 25% of individuals are currently unaware of their hyperglycemia: Approximately 1.5 million new cases of adult diabetes is diagnosed each year in the United States
• Approximately 84 million adults in the US have impaired glucose tolerance or "prediabetes", elevated blood sugar not yet to T2D level
• Compared to non-Hispanic Caucasians, Native Americans, African Americans, and Hispanics are 1.5 to 2 times more likely to develop diabetes
• World Health Organization estimates 422 million people suffer from diabetes worldwide, with India and China having the largest contributors to that figure
• Escalation of T2D and obesity: known as diabesity epidemic which some believe stems from sedentary lifestyles and eating habits.
• This epidemic has now spread to children living in "food deserts" who subsist on highly processed foods rich in carbohydrates and sugar and who do not exercise adequately.
• Mortality rate from diabetes diverges between nations, with low- and middle-income nations accounting for almost 80% of diabetes-related deaths and nearly double the rates in high-income areas
• United States still lists diabetes as a top 10 killer
• Total yearly cost associated in relation to diabetes in the United States is estimated to be $327 billion, including $237 billion in direct medical costs and $90 billion in indirect costs

Diagnosis

• Blood glucose is normally maintained in a range of 70 to 120 mg/dL: Diagnostic criteria for diabetes include:
• Fasting plasma glucose ≥126 mg/dL
• Random plasma glucose ≥200 mg/dL (in a patient with classic hyperglycemic signs)
• 2-hour plasma glucose ≥200 mg/dL during an oral glucose tolerance test (OGTT) with a 75 g loading dose
• A glycated hemoglobin (HbA1c) level ≥6.5%
• All tests, except random blood glucose test need to be repeated and confirmed on a separate day
• Discordance between two assays results in the result with the greatest degree of abnormality counted
• Acute stresses lead to transient hyperglycemia due to catecholamines and cortisol secretion, opposing the action of insulin so diagnosis of diabetes requires persistence of hyperglycemia following resolution of illness
• Prediabetes, a state of dysglycemia that often precedes blatant T2D, is shown by one plus of the following:
• Fasting plasma glucose between 100 to 125 mg/dL ("impaired fasting glucose")
• A 2-hour plasma glucose between 140 and 199 mg/dL following a 75-g oral glucose tolerance test (“impaired glucose tolerance")
• A glycated hemoglobin (HbA1c) level between 5.7% and 6.4%
• As many as 25% of individuals with impaired glucose tolerance will develop diabetes over 5 years with obesity and family history adding risk
• Individuals with pre-diabetes also are at significant risk for cardiovascular complications.

Classification

• All forms of diabetes have hyperglycemia as a shared characteristic, but the underlying mechanisms have high amounts of variety
• Current classifications reflect greater understanding of pathogenesis
• Type 1 diabetes (T1D) is an autoimmune disease with pancreatic destruction and absolute insulin deficiency. It accounts for 5% to 10% of diabetes and is subtype diagnosed in patients and patients younger than 20 years old.
• Type 2 diabetes (T2D) is due to peripheral resistance to insulin action plus a secretory response by pancreatic B cells that is inadequate to overcome resistance
• Around 90% to 95% of diabetes patients have T2D, and bulk are overweight.
• Although adults are mostly the ones with T2D, the prevalence in children and adolescents has been increasing to the increasing obesity rates particularly in ethnic groups

Comparative Features of Type 1 and Type 2 Diabetes

• Type 1 Diabetes
• Onset is childhood or adolescence
• Normal weight or weight loss typically occurs before diagnosis
• Insulin levels progressively decrease
• Islet autoantibodies circulate (anti-insulin, anti-GAD, anti-ICA512)
• Diabetic ketoacidosis occurs apart from insulin therapy
• Major linkage to MHC class II genes; also linked to polymorphisms in CTLA4 and PTPN22, and insulin gene VNTRS
• Malfunction in T-cell selection and regulation leads to breakdown in self-tolerance to islet autoantigens
• Insulitis, inflammatory infiltrate of T cells and macrophages affects
• Cell depletion with islet atrophy
• Type 2 Diabetes
• Primarily adult onset and increasing incidence in childhood and adolescence -Obese in the vast majority
• Blood insulin initially increases; normal or moderately decreases later
• No islet antibodies circulate
• Nonketotic hyperosmolar coma is more common
• No HLA linkage; linkage to candidate diabetogenic and obesity-related genes
• Insulin resistance in peripheral tissues, failure of compensation by B cells
• No insulitis; some cases are related, but other conditions are involved, Amyloid deposition occurs in the islets
• Mild B-cell depletion

Glucose Homeostasis

• Is tightly regulated by three key steps: glucose production in the liver; glucose uptake and utilization by peripheral tissues, chiefly skeletal muscle; and actions of insulin and counter-regulatory hormones
• Insulin and glucagon have opposing results on glucose levels
• Low insulin and high glucagon facilitate hepatic gluconeogenesis and glycogenolysis while decreasing glycogen synthesis, thereby preventing hypoglycemia
• Fasting plasma glucose levels are determined primarily by hepatic glucose output, insulin promotes glucose uptake in tissues
• Skeletal muscle is key for glucose levels and is vital for preventing high glucose
• Brain and adipose tissue also extract a significant amount of glucose from the circulation

Regulation of Insulin Release

• Production takes place in the B cells in the islets as a precursor protein and is proteolytically cut in the Golgi complex, C-Peptide also, Both Insulin and C-Peptide are then stored in granules that are secreted in response to hormone stimulation: C-Peptide is a surrogate in determining B-Cell function.
• Glucose is the main way for it to occur: increase generates uptake inside pancreatic cells, leads to influx through membrane calcium channels that stimulates insulin presumably from granule
• Immediate insulin release, "first phase beta-cell release" takes place in the event of stress that delays. If continued response of secretion, delays it and includes active synthesis
• Incretins are responsible for promoting release and act by binding
• 2 most important incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-type peptide-1 (GLP-1) released by intestines: Elevage in those cause incretin effect In addition they cause other steps like gastric emptying that promotes satiety.
• GLP is usually affected in patients with T2D: Synthetic binding to the receptors in the body can cause weight loss but GLP-1 receptor agonists are what allows diabetes to heal for the most part.

Insulin Action and Signaling Pathways

• Most potent hormone, having both synthetic and growth aspects
• principal metabolic function is to increase glucose rate by providing a source of intermediates like lipids and amino acids.
• Most important targets of insulin are striated muscle cells and adipocytes; the most glucose comes from "beige adipose tissue, good and exercise and not the "white tissue"
• Muscle cells store tissue as glycogen; adipose uses it as lipids for tissue storage
• Insulin Inhibits also: Synthesis and trigryceride hydrolysis and degradation of glycogen. It also exerts activities
• Insulin attaches to a signal, which exerts and activates an a and b chain

Pathogenesis of Type I Diabetes

• Autoimmune in which destruction means that effector cells target antigens and commonly develops in childhood
• The old moniker "juvenile onset" is now dropped because it can develop in many ages: " Insulin is needed for the survival; if not then ketoacidosis development and other severe complications will erupt
  • Involves genetics factors and environmental factors but mainly susceptibility
• higher chances for twins. multiple identified

genetic susceptibility

• HLA gene cluster is most important; of 90% to 95% of Caucasians in particular HLA-DR1 or HLA-DR4
• certain polymorphisms are correlated to the disease risk, still not fully understood how specific contributes
• Variable tandem repeats in the promoter of the insulin gene were the first variants identified associated with the disease
• association to that of the altered selection of T cells in conjunction also with disease

Environmental

• genetic rate contributes to part, concordance is 50%, so plays environmental Although viral is suspected, unknown.

Mechanism

• initiates autoimmune and appearance of the signs of the disease between the autoimmune and appearance

stages of TID

• Stage 1: positivity, normal levels of high glucose that is presymptomatic
• Stage 2: Autoimmune response occurs that includes, dysglycemia, glucose intolerance, and lack of symptoms.
• Stage 3: Manifests the full traits classic to the illness and loss of 90% of beta cells

Immune abnormality is one of failure for tolerance

• Failure is one from deletion and resistance to suppression for any regulatory issues Activation is thought to occur in the pancreatic lymphs in response to various damages that lead to that. CTL's kill cells and attack targets in the body. Cancer does that for the disease

Pathogenesis of Type 2 Diabetes

• genetic factors and disease without an autoimmune basis, but genetic adds: higher rates in rates Relatives of the individual have the high risks compared to other factors like weight: genes are involved in the function, however risk has an impact. Obesity plays a major role impact Important is one with visceral fat compared to obesity , the liver has the steatosi, etc. and with a small increase it can cause insulin resistance. Disruptions are those who affects sleep and behaviors
• Several Factors include:
• resistance happens, failure to to respond normally to insulin. the resistance comes from the glucose output, can cause high levels Gluteal is likely to come with a better increase.

Obesity can also affect

• FFAs, increase and sensitivity comes with those sites.
• Adipokines; hormones in releasing metabolism
• Inflammation, occurs in the cells and leads to cytokines as cells which promotes signals and effects the excess FA

B-Cell Dysfunction, Diabetes

• Resistance includes requirements, but genetics can't be ignored
• Altered genes includes issues and release
• Glycogen leads to reduced insulin Amyloid exists in the islets but its cause is unclear

Forms of Diabetes

• uncommon, can be from two types: one the a defect from one that stops production or one that affects from inside or outside.
• Most common in those under 30.

Pregnancy

• complicated which can get gestational: hormonal is important for this and must treat to maintain pregnancy in all times.
• Long term can increase risk of mortality in both T1 and T2.

Clinical Features

• with difficulty comes diverse presentations: the discussion will discuss presentation and diagnosis for the following and acute/ long term complications to follow
• in T1, exagenous leads to minmal because of residual secretion or homoeostasis with time however the tipping point arises eventually/stress such as an accident In contrast, T2 is the typical with obesity, with increased with those with sedentary lifestyle for the increasing amount: may seek for unexplained factors although is based on testing blood.
• the test blood shows large number of glucose thus:
• test are done for those above 45
• The onset for T1*

Triad from Diabetes

marked by triad of polyuria(Excess/frequent Urination), polydipsia (Excessive Thirst), and polyphagia(Excessive appetite). Defeciency results from the catobolic state which effects the cells in the process

• This catablism is brought about by the fact that a decrease in assimilation for tissues happens causing not only stoppage for glucose increase but also filters more from what is normally filtrised leading to water intake with a trigger effect that leads to the thrist/polydispia (intense thirst)

In the situation there is limited assimilation scales.swing to the caboloism to where

• Proteins/fats trigger the body and induce negative energy balance leading to increase diet thus completing the trait and circle. Weightloss happens however due to this whole occurance Combination leads to a high chance of a suspicion for diagnosis.

Metabolic Complications

• Diabetic ketoacidosis is a severe complication; does not occur severe T2 Caused from failure to take drugs trigger: infection/illness. leads to not good peripheral use while increasing and hyperglycemia causes glucose and dehydration and glucose can pass and dehydrate or worsen

• a lack of insulin causes in synthesising the bodies and hormones: Oxidation happens and is high and cannot cause more bodies however a lack of dehydration may further that and leads to acidosis. the clinical issues leads to vomiting, fatigue, fruit odor, and labored breathing that will cause depression Treatments include insulin, acidosis, and correcting from inside: acidosis is not too severe so treatments will differ: and can lead to shock

• leads to low dehydration

• Treatment comes and complications occur from excessive use.

• In deficiency coupled is glycagon excess what are the major effects in which keto can also state

Diabetes Complications

• Long standing the effects
• The long term is hyperglycemia/glucotoxicity/and to large and small vessels

Figure 24.33 Key

Defeciency (total) causes a catoblismic states which leads from eventual coma from total death: a treat can mean avoiding: causes is one such as a physical exertion. Hypoglycemia includes similar symptoms and with the rapid reversal treatment of hypoglyceima or the opposite helps in the condition/death

Complications of Diabetes:

• Long Standing diabetes may lead to high morbidity and mortality.

Mechanism to Damage of High Level of Glucose; Hyperglycemia

• Causes End - Organs by Damaging a high-power flow
• Advanced Formation: Occurs with reactions
• Rate formation is fast and binds to a specific receptor . Leads to vascular and vascular.
• Can Generate oxygen cells that is active in the Procoagulant. Endothelial activity.
• Enforces of vascular tissue synthesis

Hypertrophy and Changes

• Matrix with small vessels leads to injury and leads to vessel/tissue damage.
• The proteins may have a hard time with these so they can cause them again and the process can inhibit the cells. Thus making a high chance

Glucose Activate Protein C

Calcium will also help. The increase of downstream cause expression that are evident and some over lap Pathway: Even tissues may effect insulin: cause increase if its persistent over time this is what occurs, this is known as aldose, the reduced nicotinamide dinucleotide/ NAD

Sorbitol: can cause what can inhibit regeneration, increasing stress and cataracts

• Flux of cells will enhanced and affect stress also. Morphology : Is Related too the disease The Alterations are related to the conditions and have subtle causes with distinctive changes, also depends on the disease of the tissue, alterations are also subtle Morphology

Pancreas

The pancreas

• Inconstant and different: distinctive changes are more associated which causes rapid death.
• In the cells : Lymphocytes happen and are seen with the models Lymphocytes
• Reduced is the high cell mess: demonistrates reduction early. Amyloid is an increased between in and around at many steps

Increased is what is characteristially known where the numbers can be more hyperplasion. It exacts with a toll, many of the bad side effects, the function of cell has and is why such as: dysfunction damage and leads

Diabetic Macrovasular

• End damage affects
• *The Morphology of Athero with Patient: Cannot Distinct Damage of the Kidneys at Damage Level Increased: the pressure also affects,

Hyaline

One of important feature by the increased thickening with this it's caused increased. The microangipathy underiles Renal with necrosis and the like are more for diabetics the same to other

ocular

• can affect deeply and leads to changes
• Acquired becomes the lens
• Retinal can be classified by a background , and are and leads to retina which classified as the bloods due to their presence.

Can lead to many other problems as well that are bad, and are not the sole way too it.

Nephropathy : Leads to multiple sides, necrosis Neuropathy Damage Patients : Lead Visual; that does

Patients: Long standing does have.

Related is the attenuated damages. Macro leads from complications Complications the the risk And are increased

• Underlies that the the the

Diabete Complications . that damage that the the

The under and these