📘 Understanding type 2 diabetes

Type 2 diabetes is a progressive metabolic disease in which your body develops insulin resistance, and pancreatic beta cells can no longer compensate through sufficient production [1]. Unlike type 1, where the immune system destroys beta cells, in type 2 they function defectively. They continue to produce insulin, but insufficiently for your increased needs. It's like the difference between a destroyed factory (type 1) and one that operates poorly and cannot meet demand (type 2).

Fundamental differences include gradual onset over years (type 2) versus relatively abrupt onset over weeks (type 1), presence of endogenous insulin versus its almost complete absence, initial treatment with lifestyle modifications and oral medications versus mandatory insulin from the start, and partial reversibility in early stages (type 2) versus irreversibility in type 1 [1]. In type 2 you still have pancreatic reserve for years, you may never need external insulin if you control the disease well, and you don't risk rapid onset of ketoacidosis when treatment is omitted, as happens in type 1.

Insulin resistance occurs when muscle, liver and fat cells respond insufficiently to insulin action, requiring increasingly higher insulin concentrations for the same metabolic effect [2]. Accumulation of ectopic fat (in abnormal places) in muscle and liver interferes with intracellular insulin signaling cascade, blocking movement of glucose transporters to the cell membrane. Chronic low-grade inflammation, mediated by pro-inflammatory adipokines (TNF-α, IL-6) and oxidative stress disturb activation of insulin receptors [2].

Factors that amplify insulin resistance include excess circulating free fatty acids from increased lipolysis, mitochondrial dysfunction that reduces cellular energy production capacity, and accumulation of toxic lipid metabolites (ceramides, diacylglycerol) in insulin-sensitive tissues [1]. Initial compensatory hyperinsulinemia paradoxically further worsens resistance through receptor down-regulation (decrease in their number) and gradual reduction in beta cell numbers, which are already working in excess. It's a vicious cycle in which insulin requirements continuously increase until endogenous production becomes insufficient [2].

Type 2 diabetes cannot evolve to type 1 because they are diseases with completely different pathogenetic mechanisms [1]. In type 2 we have insulin resistance with progressive beta cell dysfunction, while in type 1 autoimmune destruction of beta cells. What may seem like a "transformation" is actually the natural progression of type 2 towards insulin-necessity, after beta cell exhaustion, but the mechanism remains non-autoimmune. Alternatively, you may have LADA (a form of type 1 diabetes) misdiagnosed initially as type 2 due to slow onset [3].

Approximately 2-12% of adults initially diagnosed with type 2 actually have LADA, demonstrable through presence of anti-GAD or anti-IA2 autoantibodies and C-peptide disproportionately low relative to disease duration [3]. Confusion arises when thin patients with "type 2" progress rapidly to insulin necessity. These are often cases of LADA or even classic type 1 with adult onset. Autoantibody testing clarifies the diagnosis and has important prognostic implications, as LADA requires insulin earlier and doesn't respond durably to oral medication [3].

Type 2 diabetes can be put into remission through intensive lifestyle interventions or bariatric surgery, especially in the first years after diagnosis, when beta cell function is still recoverable [4]. The DiRECT study demonstrated that loss of over 15 kg can induce remission in 86% of participants with diabetes for less than 6 years, maintained in 36% after 2 years [4]. Remission means HbA1c below 6.5%, without antidiabetic medication, for minimum 3 months, but requires lifelong monitoring because metabolic predisposition persists.

Reversibility depends on residual beta function, diabetes duration, degree of glucotoxicity and lipotoxicity, and ability to maintain weight loss long-term [5]. After 10 years of disease, chances of remission drop below 5% due to irreversible decrease in beta cell numbers. Metabolic surgery can sometimes induce remission even in more advanced diabetes cases, through complex hormonal mechanisms, beyond simple weight loss [6]. However, relapse occurs in half of patients in the following 5 years, especially if eating habits return to the previous pattern [6].

Residual insulin production in type 2 diabetes means that pancreatic beta cells still secrete insulin, demonstrable through positive C-peptide (above 1 ng/ml) [7]. Unfortunately the quantity and secretion pattern are insufficient for normal body metabolism. First phase of insulin secretion (first 5 minutes after stimulus) is lost early, and basal secretion becomes insufficient to restrain hepatic glucose production [1]. There is measurable circulating insulin (often even initially elevated), but its effect is diminished by tissue resistance.

Presence of endogenous insulin offers you major advantages over type 1. You have protection against ketoacidosis (residual insulin inhibits massive lipolysis), flexibility in meal and medication timing, response to oral medications that stimulate or sensitize the body to insulin action, and lower glycemic variability [7]. Periodic C-peptide monitoring helps evaluate beta cell reserve and guides need to intensify therapy. Generally, when C-peptide drops below 0.6 ng/ml, metabolic control with oral medications alone becomes very difficult to achieve [7].

Type 2 diabetes progression follows a trajectory of declining beta cell function at approximately 5% annually after diagnosis, eventually accelerated by persistence of gluco and lipo-toxicity [1]. Initially, compensatory hyperinsulinemia maintains blood glucose in targets, then postprandial hyperglycemia appears when first phase secretion is lost, followed by fasting hyperglycemia, when hepatic glucose production can no longer be suppressed. After 15 years, over half of patients require injectable treatment, added to oral therapy [8].

Microvascular complications (retinopathy, chronic kidney disease, neuropathy) may already be present at diagnosis in 20% of cases, due to long asymptomatic period, and progress exponentially with suboptimal glycemic control [9]. Cardiovascular risk is at least double, independent of other factors, and each 1% increase in HbA1c increases the risk of microvascular complications by 37% and myocardial infarction by 14% [15]. Early intensive interventions can modify the natural trajectory. The phenomenon of "metabolic memory" shows persistent benefits at 10-20 years after a period of strict control in the first years after diagnosis [10].

The outdated term "non-insulin-dependent" (NIDDM) reflected the observation that most type 2 patients can survive without exogenous insulin, unlike type 1, where stopping insulin rapidly leads to ketoacidosis and death [8]. The classification was abandoned in 1997 because it was misleading. Up to 40% of type 2 patients eventually require insulin treatment for optimal glycemic control, and some need it right from diagnosis [8]. The term wrongly suggested that insulin is never necessary and delayed initiation when it became medically indicated.

Current etiology-based nomenclature (type 2 = secretory deficit with variable insulin resistance) is more precise and guides treatment [1]. "Non-insulin-dependent" ignored disease heterogeneity. Some patients have predominantly insulin resistance with hyperinsulinemia, others have predominantly secretory deficit with normal or low insulinemia. Using the old term can delay insulin initiation when it becomes necessary, perpetuating suboptimal glycemic control and accelerating complications. In modern terms, we speak of "type 2 diabetes treated with/without insulin," to describe the current stage of disease management [8].

Type 2 diabetes incidence increases exponentially with age, reaching its peak at 65 years, when it affects 25% of the population (prevalence), in developed countries [8]. Age at diagnosis is continuously decreasing. Compared to the 1990s, diagnosis is now made at least five years earlier [11]. After 65 years, prevalence exceeds 30%, and over 80 years can reach 40%, although phenotypic heterogeneity increases with age including forms of pancreatogenic diabetes or medication-induced secondary diabetes.

Alarmingly, type 2 diabetes in young people (under 40 years) has almost doubled in the last two decades, now representing one-fifth of new cases, in some populations [11]. Early onset is associated with faster progression of beta cell dysfunction, higher risk of microvascular complications and premature mortality [12]. Children and adolescents with type 2 diabetes have a more aggressive phenotype than adults. They require insulin faster (within 5-10 years), develop complications 10-15 years earlier and have life expectancy reduced by up to 15 years compared to adult onset [12].

Beta cell exhaustion represents progressive and irreversible decline of insulin secretory capacity through multiple mechanisms [13]. Beta cell mass sometimes decreases by 50% from disease onset to diagnosis (diagnosed with significant delay) and continues to decline by 5% annually [14].

The process begins with loss of normal pulsatile secretion pattern and first phase of insulin secretion in response to glucose [1]. It then progresses to inability to suppress hepatic glucose production and eventually complete insufficiency requiring exogenous insulin. Markers of exhaustion include increased proinsulin/insulin ratio (indicator of defective processing), C-peptide below 0.6 ng/ml under stimulation conditions and presence of islet amyloid deposits, which are toxic to beta cells [14]. Once lost, adult beta cells have minimal regeneration capacity, making the process practically irreversible after a certain critical mass is lost [13].

Type 2 diabetes represents 90% of all diabetes mellitus cases [8]. Prevalence has increased dramatically in the last four decades. In developed countries, prevalence is approximately 10% of the entire adult population, but can exceed 30% in people over 65 years [8]. Lifetime risk of developing type 2 diabetes ranges from 30-40% in Western countries, increasing to 40% for those with one diabetic parent and to 70% when both parents have diabetes.

Frequency increases exponentially with age, obesity and sedentary lifestyle, being three times higher in people with body mass index over 30 kg/m² [8]. There are significant ethnic variations, with rates at least double in populations from South Asia, Middle East, Africa and Latin America compared to Caucasians. Millions of people have still undiagnosed type 2 diabetes. Globally, nearly half (45%) of those affected don't know they have the disease, with the proportion dropping to about 30% in developed countries [8]. Incidence in children and adolescents has almost doubled in the last two decades, a phenomenon associated with the childhood obesity epidemic [11].